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There are several directions for further development of erectile dysfunction treatment market nowadays. Current PDE-5 inhibitors are likely to become more advanced and more people are expected to get access to their generic versions as well as over-the-counter PDE-5 inhibitors. Researchers are also looking to enhance other ED medications that show promising results, including various topical creams and dopamine and melanocortin activators. There are several brand-new medications, which affect male sexual function in entirely different ways compared to current ED drugs, being studied and likely to be released in the nearest future. These include chloride channel blocking drugs, soluble guanylate cyclase stimulators and activators and Rho-kinase inhibitors. Finally, there are also several non-pharmaceutical ways of ED treatment that have undergone successful clinical trials including gene and stem cell therapy and low intensity shock therapy.

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The Future of ED Treatment

Erectile dysfunction treatment is a multi-billion-dollar industry nowadays, so a person suffering from this condition has got multiple options to choose from including pharmaceutical medicines (PDE-5 inhibitors, vasoactive agents), surgery (penile prostheses, revascularization surgery), use of vacuum constriction devices and counseling. Since all these options have certain flaws, such as efficacy rate below 100%, possible side effects, etc., the search for new, better remedies continues. In the article below we will list the most recent developments that could shape the future of ED treatment.

Vasoactive agents used in ED treatment include prostaglandins, papaverine, phentolamine, etc. When injected into the penis or used topically, these substances expand the blood vessels allowing more blood to enter the penis and thus triggering an erection. Vasoactive substances are usually chosen as second-line ED treatment when PDE-5 inhibitors do not work or cannot be used by the patient for some other reason. The efficacy rates range between 46% for topical medications and over 90% for injections. Most common side effects include penile pain, bruising and fibrotic complications at the injection site, prolonged erections.

Revascularization surgery is a technique used to treat erectile dysfunction caused by trauma to the perineum, pelvis or penis itself or arterial pathologies. It aims to bypass the affected blood vessels and deliver blood flow from the inferior epigastric artery to the dorsal penile artery. The efficacy rates are 85% 3 years past surgery and 67.5% 5 years past surgery. Complications like disruption of the scar tissue and decreased penile sensation due to nerve damage are possible but not common.

PDE-5 Inhibitors

Erection pills like sildenafil, tadalafil and vardenafil are currently the most popular means of treating impotence and they are clearly not going anywhere soon. However, there are some changes expected even in this stable market in the nearest future:

The market share of generic PDE-5 inhibitors will keep growing

In 2017, Pfizer sold $1.2 billion worth of Viagra, down from over $2 billion in 2012 and this year the numbers are expected to go down to an all-time low of around $360 million. The decrease in revenue is not due to lowering interest though, the pharmaceutical mogul’s earnings are dropping after its patent expiry as more and more manufacturers are entering the market. Even in the US where the manufacturers of brand-name ED meds have faced no competition until recently, Pfizer’s market share is down to 15%. Eli Lilly’s (manufacturer of Cialis) share is about the same and the rest is all distributed among different pharmaceutical companies making vardenafil, avanafil, udenafil and, of course, generic sildenafil.

Generic PDE-5 inhibitors cost up to 98% cheaper than brand-name pills but have the same effect and efficacy rates since they contain the same active ingredients and are available in the same strengths. Taking that into account along with the fact that generic tadalafil and vardenafil are soon expected to enter the markets where Cialis and Levitra are still patent-protected, we can conclude that the sales of cheap but reliable generic ED medication are likely to keep growing worldwide.

PDE-5 inhibitors will become widely available without prescription

While PDE-5 inhibitors are still available by prescription in the US and many other places around the world, some countries are lifting the restrictions and making Viagra and similar drugs available over the counter. New Zealand was one of the first countries to allow prescription-free sales of Silvasta, a generic sildenafil-based ED medication. In 2018 an over-the-counter version of Viagra named Viagra Connect was released in the UK. According to traveler reviews, one can get brand-name and generic ED medications without prescription in countries like Mexico and Thailand too.

The statistics regarding the incidence of side effects, abuse, etc. in OTC ED medication buyers are closely monitored by the governments of the countries listed above. If the overall experience proves to be positive, then more countries are likely to make PDE-5 inhibitors available over the counter.

More advanced PDE-5 inhibitors will appear

The market of PDE-5 inhibitors is not limited to sildenafil, vardenafil and tadalafil only. Among the most recently developed ED drugs from the same group are avanafil, udenafil, mirodenafil and lodenafil, the so-called ‘second generation PDE-5 inhibitors’ that feature enhanced selectivity and can be taken daily. As these medications are approved for use in more countries, the global market will become more saturated. New, more advanced drugs from the same class are also likely to appear in future.

Avanafil – a PDE-5 inhibitor used in the treatment of erectile dysfunction. Invented in 1999 by the researchers from Mitsubishi Tanabe Pharma Corp, patent issued in 2001, FDE approval in 2012, EMA approval in 2013. Marketed under brand names Stendra and Spedra. Its main advantage over similar drugs is more rapid onset of action – it starts working 15-45 minutes after being taken whereas other PDE-5 inhibitors take up to an hour.

Udenafil – a PDE-5 inhibitor used to treat erectile dysfunction and BPH and available in South Korea, the Philippines, Malaysia and Russia under the brand names Zydena, Udzire, etc. Similarly to tadalafil, can be used both as needed and on a daily basis, the latter due to its long half-life of 11-13 hours.

Mirodenafil – a second-generation PDE-5 inhibitor available in South Korea as Mvix.

Lodenafil - a second-generation PDE-5 inhibitor available in Brazil as Helleva.

Promising Pharmaceutical ED Treatments in Need of Improvement

There are various medications that are or were used for ED treatment but have lower efficacy rates or more severe side effects compared to PDE-5 inhibitors. The researchers are working on enhancing such alternative ED medications listed below.

Topical ED Drugs

1% alprostadil cream, available under the brand names Vitaros and Virirec in Canada and the EU, is a common second-line ED treatment usually prescribed to patients who can’t take PDE-5 inhibitors for some reason. It has an efficacy rate of around 39%.

Multiple researches focusing on the use of topical PDE-5 inhibitors for the treatment of ED have been carried out in Iran, South Korea and Egypt. Although the tested creams and gels proved to be safe, the bioavailability of active ingredients was low, affecting the potential efficacy in the negative way.

Both abovementioned ED medications can potentially be improved by using percutaneous absorption enhancers to facilitate the transdermal absorption of the medication. If the clinical trials of such improved formulations show satisfactory results, we will see more effective topical ED treatments soon.

Another promising topical ED cure, MED2005 (Glyceryl Trinitrate) developed by Futura Medical has now proceeded into Phase III clinical trials after its effectiveness has been documented in almost 70% of participants. MED2005 is a vasodilator that is supplemented with a potent transdermal delivery system. It starts working as soon as 5-10 minutes after being applied to the penis.

Dopamine receptor activators

The release of a neurotransmitter called dopamine precedes penile erection in males. By taking dopamine receptor activators like apomorphine, patients with ED can enhance their response to sexual stimulation and develop erection hard enough for intercourse. Apomorphine-based drugs Uprima and Ixense had been licensed for sale in the EU and the UK in 2001 but the license was later withdrawn at the manufacturers’ request due to commercial reasons. In the US, in its turn, apomorphine didn’t receive the FDA approval due to potentially severe side effects including hypotension.

Two medications similar to apomorphine but having fewer side effects, ABT 724 and ABT 670, were developed and tested in 2004-2006 but their efficacy was lower compared to the original medication (62.7%). Thus, the search of dopamine receptor activators that are both highly effective and do not cause serious adverse reactions continues.

Melanocortin activators

Similarly to sildenafil, another ED treatment with high potential, Melanotan I, was discovered by accident. It was originally developed as a skin-melanin pigmentation enhancing drug but triggered spontaneous erections in male patients during clinical trials. Its enhanced form, Melanotan II, also had the same effect but further research of its effects on sexual performance revealed that it caused multiple adverse reactions and took over 2 hours to start working. Another metabolite of Melanotan called bremelanotide worked much faster when taken as a nasal spray but had side effects too. A pharmaceutical company called Palatin Technologies is currently researching the use of subcutaneous bremelanotide for ED treatment and reporting positive results. The subcutaneous form of the medication is also undergoing trials as a treatment of sexual dysfunction in postmenopausal female patients.

Brand-New Pharmaceutical ED Treatments Being Researched

Chloride channel blocking drugs

The article by K.I. Hannigan et al focusing on the potential of chloride channel blocking drugs in treating erectile dysfunction, as opposed to other researches, studies the processes causing the penis to become flaccid after sex, and not the processes that trigger the erection. When the smooth muscles in erectile tissue contract pushing the blood out of the penis, chloride moves out of the muscle cells and calcium moves in. Preventing the outward flow of chloride results in longer, stronger erections, which helps both those patients who can’t reach a sufficient degree of hardness for penetration as well as those who lose erection soon after the beginning of the intercourse.

Soluble guanylate cyclase stimulators and activators

Soluble guanylate cyclase (sGC) is one of the three most important chemical mediators of penile erection. An erection is preceded by the release of nitric oxide by the nerve cells in the penis, which then triggers the release of sGC and, consequently, the release of cyclic guanosine monophosphate (cGMP). Current PDE-5 inhibitors (sildenafil, tadalafil, etc.) work by stimulating the release of cGMP whereas new drugs known as soluble guanylate cyclase stimulators and activators go one step ahead and ensure proper response to sexual stimuli by affecting sGC release. These new medications can potentially be used for treating not only erectile dysfunction but also lower urinary tract symptoms, including those related to BPH in men.

Rho-kinase inhibitors

Another new approach to treating erectile dysfunction arises from the low efficacy of PDE-5 inhibitors in certain groups of patients including those with diabetes. Treatment with Rho-kinase inhibitors avoids the “nitric oxide – sGC – cGMP” pathway altogether and targets an entirely different chemical in the body. Rho-kinase plays an important role in maintaining penis in flaccid state, so by inhibiting it we can potentially stimulate erection in response to sexual stimulation. Rho-kinase inhibitors have already been tested on lab rats and proven effective in treating age-associated ED and ED caused by diabetes. Tests on human subjects are yet to be conducted.

Non-pharmaceutical ED treatments of the future

Gene therapy

Gene therapy-based approach to treating ED is based on the concept of gene transfer that would stimulate the natural production of chemicals involved in the process of penile erection. One of the recent studies has already proven the effectiveness of gene therapy – a group of Swiss scientists have developed a gene construct that can stimulate the release of cGMP on demand. When injected into the erectile tissue of the penis, this gene construct can trigger an erection when the patient is exposed to blue light. The blue light can potentially be replaced with another stimulus, which could provide an easily administered ED treatment that, unlike current alternatives, doesn’t depend on sexual stimulation.

Stem cell therapy

A recent work published by a group of Danish scientists shows that stem cell therapy is effective in patients with erectile dysfunction. The researchers used stem cells obtained from the patients’ abdominal fat tissue and injected them into their penises using microneedles. As the result, 8 out of 21 men participating in the researched claimed to have recovered their sexual function. The effect is due to the ability of mesenchymal stem cells to repair damaged cells and tissues in human body – including the cells and tissues involved in the mechanism of erection. Other researchers state that stem cells derived from bone marrow, placenta and urine can also be used in ED treatment, the latter two being easiest to obtain.

Low intensity shock therapy

Low intensity shock therapy involves prolonged use of a special device that applies weak electric shockwaves to certain parts of the penis, resulting in its revascularization. Its effect has been proven by at least 14 studies involving over 800 patients but the average IIEF score in patients after treatment was only 2 points higher than before treatment, meaning that the improvement was significant but not radical. Patients with mild to moderate erectile dysfunction reported better results that patients with severe ED. This means that the method needs to be improved further.

International Index of Erectile Function (IIEF) – an internationally accepted way to assess male sexual function. Rates a patient’s ability to reach and maintain an erection, its hardness, the ability to engage in satisfactory sexual intercourse, and subjective confidence levels on a scale of 5 (severe ED) to 25 points (no ED).

All in all, it’s clear that the erectile dysfunction treatment market keeps developing with many new pharmaceutical and non-pharmaceutical means of fighting impotence already available for purchase or undergoing late stages of clinical trials. This gives hope not only to patients who don’t respond to traditional treatments but also to those in search of a way to make their sexual life more natural and spontaneous.

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Comments:

Hurry up and release these new drugs!

Olgerd,