Erectile Dysfunction: New Drugs for Non-Responders

Erectile dysfunction (ED) is a pretty common problem. It affects a large percentage of men all over the world. When you have ED, you can’t reliably get and keep an erection that’s firm enough for satisfying sex.

The numbers vary depending on age and other factors, but global estimates put ED rates between 10 and 20 percent. In the United States, about 52 percent of men between 40 and 70 years old report having ED. That number jumps to over 70 percent in men over 70.

The most common treatments right now are PDE5 inhibitors like Viagra and Cialis. These medications work for many men, but they’re not perfect. They only work for about 60 to 70 percent of men who try them. That leaves a large group of men looking for other options. Plus, some men experience side effects or can’t take PDE5 inhibitors because of other health conditions.

That’s why researchers are working hard to develop new ED therapies that work in different ways and meet the needs of more men. Some research focuses on the brain, while other research focuses on the tissues in the penis itself.

In this article, we’ll take a look at some of the most promising erectile dysfunction new drugs in development, including new PDE5 inhibitors, medications that work on the brain, medications that work on the penis, and even regenerative therapies.

Understanding the physiology of erection and dysfunction

Erection is a tricky thing. It’s not just about blood flow. It’s a complex interaction between your central nervous system, peripheral nerves, and the blood vessels in your penis.

The Neurovascular Basis of Erection

When you’re sexually stimulated, your body releases nitric oxide (NO) in the corpus cavernosum – that’s the spongy tissue in your penis.

NO then activates an enzyme called guanylate cyclase. This leads to increased levels of cyclic GMP (cGMP). Cyclic GMP is the key player here; it relaxes the smooth muscles in your penis and widens the blood vessels (vasodilation).

This relaxation and vasodilation allow blood to flow freely into the penis, causing it to become erect. Maintaining a balance between muscle relaxation and contraction is crucial for a good, strong erection.

Mechanisms of Erectile Dysfunction

Erectile dysfunction (ED) can happen when something disrupts this process. There are lots of potential culprits:

• Neurological disorders
• Hormonal imbalances
• Vascular diseases
• Psychological issues, such as those potentially influenced by medications like Sertraline (Zoloft)

In fact, organic causes are behind up to 80% of ED cases.

A common problem is disruption of the NO/cGMP pathway. If your body isn’t producing enough NO or cGMP, or if something is interfering with their action, you can have trouble getting or maintaining an erection.

Other factors can also play a role, like increased activity of an enzyme called Rho-kinase, decreased activity of Maxi-K channels (which help regulate blood flow), and problems with signals from the central nervous system. It’s a delicate balance, and a lot can go wrong.

Why we need new ED drugs

PDE5 inhibitors, like Viagra, are typically the first line of defense against erectile dysfunction. But they don’t work for everyone. While many men—up to 60%—respond well to these drugs when taken as needed, roughly a third don’t see any benefit.

Also, PDE5 inhibitors aren’t safe for everyone. If you’re taking nitrates, you can’t take them. And even if they’re safe for you, they can cause unpleasant side effects like headaches, flushing, and vision problems. Some men simply prefer other options.

That’s why researchers are working hard to develop new therapies to overcome the limitations of existing treatments and offer more choices. Early results from some of these new therapies are promising, especially for men who don’t respond to current treatments.

Centrally acting emerging treatments for ED

Some researchers are exploring treatments that act directly on the brain to address erectile dysfunction. These emerging treatments target neurotransmitters and receptors that play a crucial role in sexual function.

Melanocortin receptor agonists

Melanocortin receptors in the brain are involved in sexual function. Activating these receptors can boost sexual desire and improve erections.

Bremelanotide, sold under the brand name Vyleesi, is a melanocortin receptor agonist that’s been studied for ED. In one study of 342 men who didn’t respond to sildenafil (Viagra), 34% of those taking bremelanotide reported significantly better results than those taking a placebo (9%).

PT-141 is another melanocortin receptor agonist under investigation. In a phase 1 study, 32 healthy men took either a 10 mg dose or a 20 mg dose. Both doses resulted in a significantly greater duration of rigidity at the base of the penis.

Melanocortin receptor agonists have some potential upsides. Since they act on the brain, they may be able to treat both ED and hypoactive sexual desire disorder (HSDD), also known as low libido.

Dopamine receptor agonists

Dopamine is a neurotransmitter that plays a role in sexual arousal and motivation.

Dopamine receptor agonists like apomorphine SL have been studied as possible treatments for ED. Apomorphine SL is a tablet that dissolves under the tongue, which allows it to be absorbed quickly and bypass the digestive system.

Peripherally Acting Emerging Treatments for ED

While PDE5 inhibitors like Viagra have revolutionized ED treatment, researchers are still exploring new avenues that work on the penis, rather than systemically. These peripherally acting treatments aim to improve efficacy, reduce side effects, or offer a faster onset of action.

Novel PDE5 Inhibitors

The goal here is to build a better mousetrap, er, ED drug. Several new PDE5 inhibitors are in development, hoping to improve on existing drugs. Some examples include:

• Udenafil: This is in Phase III trials involving over a thousand patients.
• Mirodenafil
• Lodenafil Carbonate
• Avanafil: This one is designed to work faster than sildenafil (Viagra) and tadalafil (Cialis).
• SLx-2101

Researchers are also experimenting with topical creams and sublingual (under the tongue) versions of PDE5 inhibitors.

Guanylate Cyclase Activators

Guanylate cyclase is an enzyme that helps create cGMP. Think of cGMP as the “go” signal for smooth muscle relaxation in the penis, leading to increased blood flow. These drugs activate guanylate cyclase, boosting cGMP levels and promoting vasodilation. Examples include YC-1, Bay-2272, and A-350619.

There are also particulate guanylate cyclase (pGC) activators, like atrial natriuretic peptide and uroguanylin, that might have potential for treating ED. More research is needed.

Rho-Kinase Inhibitors

Rho-kinase does the opposite of cGMP; it encourages smooth muscle contraction. By inhibiting Rho-kinase, these drugs can help relax the penile muscles and improve blood flow. Examples include Y-27632, Fasudil, and SAR-407889.

Maxi-K Channel Openers

Maxi-K channels are potassium channels that control the electrical charge of smooth muscle cells. Opening these channels makes the smooth muscle cells more relaxed, leading to vasodilation and better blood flow. Examples include NS1619 and BMS-223131.

Nitric Oxide Donors

Nitric oxide is a key player in vasodilation. These drugs provide nitric oxide directly to the penile tissue, encouraging better blood flow and erection. Examples include L-arginine and glyceryl trinitrate (the same drug used to treat chest pain).

Regenerative Therapies for Erectile Dysfunction

Beyond pills, creams, and injections, researchers are exploring regenerative therapies that could restore erectile function.

Stem Cell Therapy

Stem cell therapy involves injecting stem cells directly into the penis. The goal? To repair damaged tissue and improve erectile function. Stem cells are unique because they can transform into different types of cells, including smooth muscle cells and endothelial cells. These cells play a vital role in achieving and maintaining an erection.

Stem cell therapy shows promise, particularly for certain types of ED, but more research is necessary before it can be considered a mainstream treatment.

Therapies Using Physical Energies

Researchers are also investigating therapies that use sound waves and ultrasound to treat ED.

Low-intensity shock wave therapy (LI-SWT) delivers acoustic waves to the penis, stimulating angiogenesis (the formation of new blood vessels) and improving blood flow. A meta-analysis showed a meaningful difference of 4.23 points on the erectile function domain of the International Index of Erectile Function (IIEF) score between LI-SWT and sham groups. In a study, 40.5% of the men receiving LI-SWT experienced a clinically meaningful improvement in erectile function.

Low-intensity pulsed ultrasound (LIPUS) is another therapy under investigation. It uses ultrasound waves to stimulate tissue regeneration and improve erectile function.

Combination Therapies and Personalized Approaches

The future of ED treatment may involve combining different drugs to boost effectiveness and minimize side effects. For example, researchers are exploring the potential of combining melanocortin agonists with PDE5 inhibitors, the class of drugs that includes Viagra and Cialis.

Another key trend is tailoring treatment to the individual. ED can stem from a variety of underlying causes, so a personalized approach that addresses the specific issues of each patient is likely to be more successful.

Finally, don’t underestimate the power of communication. Counseling for both patients and their partners can improve how well PDE5 inhibitors work, highlighting the importance of addressing the psychological aspects of ED.

Frequently Asked Questions

Conclusion

The way we treat erectile dysfunction is changing quickly. New therapies are being developed all the time, offering new ways to address the limitations of the medications we already have and give men with ED more choices.

Future research should focus on carefully designed clinical trials to confirm that these new therapies are safe and effective in the long term. We’re also likely to see more personalized approaches to treating ED, taking into account the underlying causes of each man’s condition and his unique needs.

Innovation is essential for improving the quality of life for men around the world. Men deserve treatments that are:

• effective
• safe
• easy to use

With continued research and development, we can expect even more advancements in ED treatment in the years to come, helping men regain confidence and improve their overall well-being.