Erectile dysfunction is a very common condition affecting up to 50% of men aged 40 to 70.
The oldest written source mentioning impotence dates to 8th century BC when people tried to treat this condition with herbal concoctions and magic rituals.
The first effective surgery that helped relieve ED was performed by Francesco Parona. Pharmacological treatments popular in the past included natural hormonal extracts (early 1900s) and intrapenile injections (1980s). The first of modern peroral ED drug (PDE-5 inhibitor), Viagra, was invented in 1988 and approved for use in 1998, followed by Levitra and Cialis.
New ED drugs currently in development: topical creams, melanocortin/dopamine activators, stem cell and genetic therapy, chloride channel blockers, new-generation PDE-5 inhibitors (similar to Viagra but with improved performance).
ED drugs: from the Past to The Future
Today’s article is dedicated to the history of erectile dysfunction treatments – from the oldest ones used by the healers of the ancient past to the first successful surgeries of the 19th century AD and then on to oral ED tablets like Viagra and even more progressive treatments currently in development.
People are prone to numerous diseases, one of which is erectile dysfunction. Little is known about it since men prefer not to discuss their sexual problems openly, although most patients with ED are willing to do whatever it takes to perform in bed again. According to a Boston University study, the rate of incidence of severe or complete erectile dysfunction averages 10% in men aged 18 to 70 and peaks at 49% by 70. The Massachusetts Male Aging Study, claims the numbers might be as high as 52% in all older men aged between 40 and 70.
There are many ways of treating ED including:
- traditional treatments;
- PDE-5 inhibitors;
- alternative pharmaceutical treatments (hormonal, nitric oxide meds, etc.)
ED Drugs from the Past
Men often think that ED is a modern problem resulting from sedentary lifestyle and higher levels of stress. However, one of the first recorded references to this condition dates to the 8th century BC. Ancient Hindu, Chinese and Arabic healers would rely on magic rituals or various natural concoctions when treating ED. Some of the latter would consist of various herbs, oils and seeds while others included eggs or testes of different animals, by consuming which a man would ‘steal’ the sexual energy of a young and virile animal.
The first successful cases of surgical ED treatment took place in the 19th century when the doctors understood that erectile dysfunction could be caused by blood circulation disorders. Francesco Parona performed the first reported penile venous ligation operation with a successful outcome in 1873 – an impotent patient in his 30s managed to engage in a healthy sexual intercourse 5 days after surgery.
The first hormonal ED treatments were invented in early 20th century. The implantation of testicular substances of many animals into humans’ bodies resulted in reported potency improvements. Alongside animal implants, Serge Voronoff used testicle grafts from fresh cadavers to restore older men’s virility. This technique was reported effective as well but, due to limited supply of human organs, the surgeon would mostly perform xenotransplantations.
In 1980, Ronald Virag reported ‘accidentally’ performing an intrapenile injection of papaverine in one of his patients, which resulted in an erection. Follow-up tests proved very high efficacy of the treatment with 66% of the patients reporting significantly improved erection quality.
Similar results were observed during the studies by British scientist Giles Brindley who used phentolamine instead of papaverine to produce an erection after injection of the medicine into the penis.
From 1998 until Now: The Era of PDE-5 Inhibitors
Discovered in 1989 and approved for treatment of erectile dysfunction in 1998, sildenafil (commonly known as Viagra) was a breakthrough medication. It showed a very high efficiency rate ranging between 60% and 80% according to different sources. The side effects were relatively rare and moderate and, most importantly, the new drug was available in oral form, which saved the patients from painful injections and potentially risky surgery. Viagra was followed by vardenafil (Levitra), tadalafil (Cialis) and, most recently, avanafil (Stendra). These meds offer lower incidence of side effects (just 5-12% of patients on Stendra compared to 21% on Viagra), shorter time to the onset of action (16-20 minutes for Cialis vs 30 minutes for Viagra) and longer duration of action (36 hours for Cialis vs 4 hours for Viagra). Viagra has long remained the unrivaled leader in the market and only recently gave the first position away to Cialis, according to IMS Health data. On the other hand, such resources as Grand View Research in the US and The Pharmaceutical Journal in the UK claim that Viagra’s current position is as strong as ever.
The Future of ED Drugs
Let’s look at some of the new-generation ED drugs that are currently in development. As of 2018, some of them are already available for purchase (dopamine activators in Europe and udenafil in South Korea, for example) while others are still undergoing trials with the exact release dates unknown.
Treatments in Development
Topical ED Drugs
Creams and gels that help get and maintain an erection that could be used during foreplay are not conceptually new. They would be welcomed by those who can’t or don’t want to take ED drugs in tablet form for some reason.
The mechanism of action of a topical ED treatment is different from that of oral medications. Transdermal administration of glyceril trinitrate results in an increased release of nitric oxide, which relaxes the smooth muscles in blood vessel lining widening the vessels and allowing more blood to enter the penis.
The topical ED drugs are currently undergoing clinical trials by Futura Medical (as MED2005) and MacroChem (as Topiglan) and are expected to offer high effectiveness rates and revolutionary short time to the onset of action – as short as 10 minutes in 70% of the patients.
Dopamine activators help patients experiencing ED due to psychological problems by increasing the concentration of hormone dopamine and have already been approved for use in the EU (Denmark, Sweden, Netherlands, Spain, Italy and more). Higher levels of dopamine in the brain are associated with sexual excitement and improved physical sensations, so this medication is used in patients with ED caused by performance anxiety, fear or depression as well as other psychological problems.
Melanocortin activators are still undergoing clinical tests with the results looking promising. For example, a study by Shadiack et al. performed on both lab animals and humans has shown that increased levels of melanocortin may result in an erection.
Stem Cell Therapy
There have been around 40 full-scale works focusing on the use of stem cells in the treatment of erectile dysfunction published and at least 2 studies that proceeded into the clinical trial phase. Mesenchymal stem cells derived from umbilical cord blood could be used to stimulate an increase in the numbers of smooth muscle cells inside corpora cavernosa of the penis, resulting in improved blood flow and better erections.
Gene therapy is heavily regulated in most countries of the world including the US and most of the EU. However, there are currently a number of scientists in Switzerland, the US and other countries researching the possibility of using genetic material to treat ED.
As we age or suffer from diseases, our bodies’ ability to synthesize certain substances necessary for the sexual function (such as nitric oxide, for example) may be compromised. By adding new genes, one could potentially reverse this process and help people with ED get erection the way they did when they were younger.
This hypothesis has been successfully tested on animals already, so the next step to be taken in future would involve clinical tests on humans.
Chloride Channel Blocking Drugs
Studies show that the results of treatment with PDE-5 inhibitors remain suboptimal in around 30% of men. Plus, in those suffering from diabetes this showing may reach 41%.
The effect of chloride channel blocking drugs is based on a different mechanism, so they might help patients unresponsive to PDE-5 inhibitors. When chloride moves out of the cells in the erectile tissue, it causes the smooth muscles in blood vessels to contract preventing the flow of blood into the penis. By blocking chloride flow we could both stimulate a harder erection and make it last longer.
There are currently at least two new drugs in development (T16Ainh-A01 and CaCCinh-A01) that showed an ability to relax the smooth muscles in the blood vessels of male rabbits during animal studies and may make it to the clinical trial stage.
New-Generation PDE-5 Inhibitors
Avanafil, released into the market a few years ago, is the PDE-5 inhibitor with the lowest incidence of adverse reactions with side effects reported by as few as 5-12% of the patients.
Newer PDE-5 inhibitors currently being tested may offer longer duration of effect exceeding 36 hours. Another medication from this group (developed in South Korea and already sold there), udenafil or Zydena, is effective not only in treating ED but also improving the cognitive function.
However, Dr. Ira D. Sharlip from the University of California San Francisco Medical School, for instance, is confident that the saturation of ED drug market as well as the growing popularity of cheap generic meds will make pharmaceutical companies less interested in developing new impotence treatments. In that case Viagra and similar meds might become the final link of the ED drug chain after all.
The good part is that impotence is no longer the serious and almost incurable disease it once was. Today around 30% of men over 70 are still sexually active, so why not look for an ED drug that works for you?
- Epidemiology of ED - http://www.bumc.bu.edu
- Incidence of ED in Massachusetts – https://onlinelibrary.wiley.com
- First references to erectile dysfunction - https://onlinelibrary.wiley.com
- Francesco Parona - https://www.sciencedirect.com
- Serge Voronoff - https://en.wikipedia.org
- Ronald Viraq - https://www.ncbi.nlm.nih.gov
- Giles Brindley - https://onlinelibrary.wiley.com
- Viagra efficacy rate – https://www.europeanurology.com
- Side effects occurrence rate of avanafil-based treatments - https://www.stendra.com
- Time to the onset of action of tadalafil - https://www.ncbi.nlm.nih.gov
- Duration of action of Cialis - https://www.cialis.com
- Cialis takes over Viagra on ED medication market - http://www.medical-specialists.co.uk
- Viagra’s market position in the US - https://www.grandviewresearch.com
- Viagra’s market position in the UK - https://www.pharmaceutical-journal.com
- Effectiveness of topical creams for ED treatment - https://www.futuramedical.com
- A Shadiack et al on melanocortin activators for ED treatment - https://www.ncbi.nlm.nih.gov
- Gene therapy for ED treatment – Switzerland study - https://medicalxpress.com
- Gene therapy for ED treatment – US study - https://abcnews.go.com
- Sildenafil efficacy rate -
- Chloride channel blockers research - http://www.the-aps.org
- Ira Sharlip - http://www.scielo.br
- Sex in the older American population over 70 - https://www.verywellhealth.com
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