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Novel Therapies in treatment of Erectile Dysfunction

Novel Therapies to treat Male sexual Dysfunctions.

A normal sexual response in men and women begins in the presence of sexually oriented stimulation. When the mood is right, the body responds by releasing a cascade of chemicals that direct the flow of blood into the sexual organs. In women, this leads to engorgement and lubrication of the organs as the body prepares for intercourse. In men, this rush of blood is directed into a pair of pockets, known as the corpus cavernosum, that run inside the shaft of the penis. This inflow of blood is critical to the enlargement and stiffening of the penis.

This engorgement is triggered by a unique neurotransmitter called nitric oxide (NO). Nitric oxide, in turn, stimulates the production of another signaling enzyme called cyclic guanosine monophosphate, or cGMP for short. Under normal circumstances, cGMP signals the smooth muscles surrounding the arteries of the penis to relax and allow blood to flow into the penis. Any condition that interferes with the signaling of these messenger enzymes can quickly lead to the breakdown of the entire process and cause impotence.

The Common male sexual dysfunctions seen largely are Erectile Dysfunction and Early Ejaculation.

Erectile dysfunction, is defined as the inability to attain or sustain an erection adequate for satisfactory sexual intercourse. Erectile Dysfunction usually has a physical cause, such as disease, injury, or drug side effects. Any disorder that impairs blood flow in the penis has the potential to cause impotence. It occurs as men age: about five percent of men at the age of forty, and between fifteen and twenty five percent of men at the age of sixty-five experience impotence (Fig. 1). Yet impotence is not an inevitable part of aging

Erectile Dysfunction equates Penile Attack. Penile Attack equates Heart attack as there is enough evidence to prove the fact the Erectile Dysfunction or  Penis Attack is the earliest marker of Myocardial Infarction. Infact  India is the Diabetes Capital of the world, So India is also the Erectile Dysfucntion  Capital of the world. We have the expertise and scientific wisdom for the same and so 3.6 millions lives can be saved.

There have been a tremendous breakthrough in managing Erectile Dysfunction.

In 1998 FDA approved Sildenafil a PDE5 inhibitor for treatment of ED and this was the beginning of a new era in the treatment of ED. With three effective and safe phosphodiesterase type 5 (PDE5) inhibitors, today clinicians have multiple choices  for treating patients with erectile dysfunction of all severities and etiologies. How ever there are 20-30 percent nonresponders . The possible stratergies to these non responders was a challenge. A proper counselling , switiching over to alternate PDE5inhibitors, chronic use of the PDE5 inhibitors or alternate measures were then adopted. Chronic use of PDE5 inhibitors in low dose proved to be having a favourable pharmacokinetic profile and good therapeutic option with better compliance. A new biomarker platelet cyclic GMP was also used to prove the same. So Chronic therapy with low dose of PDE5 inhibitors was thus a valid choice.

The newer formultations which emerged were oral dispersable Verdanafil, which proved to be more than 44% efficacious, with less side reactions.

Then came the invention of Avanafil and Udenafil which increased the CGMP concentration but due to cost constrains did not have a great acceptabilty.

The other treatment modalities include Injections of Papaverine, Phentolamine, Prostaglandins , as Caverject, Bimix or Trimix given intracorporally with caution and keeping in mind prapism and counselling the patient on this complication and management of the same.

Besides this a novel therapy which is noninvasive also showed promising results i.e. Low Intensity Extracorporal shockwave therapy which increased the penile blood flow and showed  imporvement in the IIEF scores.

The other therapies which are still in the research are as follows:

Guanylate Cyclase Activators and Stimulators:It has been also observed that sGC stimulators and sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. The use of these show a promise in the treatment of ED in Diabetics.

Are we really trying to get some breakthrough in treating  difficult & stubborn ED ??

A combination of BAY 60-452 along with verdanafil have shown proerectile facilitatory effects in rats whose cavernous nerves were crushed.

One new aspect  which was then studied also shows a great deal of promise in the treatment of ED is. Rho-Kinase inhibitors.

Rho-kinase phosphorylates and inhibits the regulatory subunit of myosin phosphatase within smooth muscle cells. This action maintains phosphorylation of myosin filaments and contractile tone within the smooth muscle. So Inhibition of the calcium sensitization pathway with Rho-kinase inhibitors offers a therapeutic option for the treatment of ED that does not involve the direct targeting of the NO/sGC/cGMP pathway.

If pills dont fill  we now have low intensity extracorporal shock wave therapy which is non invasive and has shown promising results.

SHH:  Sonic Hedgehog  using alligned peptide ampiphile nanofibers plays a significant role in peripheral nerve regeneration and has clinical potential to be used as a regenerative therapy for the Cavernous nerve regenerations.

Injections of L Cystine  also has shown to produce good erections in rats.

Lastly Gene therapy and stem cell therapy also has been used in treatment of ED in Diabetics, by enhancing the NO production or NO mediated signalling pathways, K + Channel actvity of the SMCC.

Mesenchymal Stem cells along with VEGF injections have also been tried.

 

While Oral medications have showed good results there are serious Side Effects of  PDE5 inhibitors
While Sildenafil  is effective for millions of men, the side effects for many —facial flushing, headaches, and indigestion— are too troublesome for continued enjoyment. And, more seriously, soon after its introduction, vision problems began to surface in men taking Sildenafil, leading to warnings for people with retinal eye conditions, such as macular degeneration or retinitis pigmentosa, to use the drug only with caution.

In addition to eye problems, both the FDA and the manufacturer began to issue warnings against taking Sildenafil with any nitrate-based cardiac medications (i.e., sublingual nitroglycerin tablets, nitroglycerin patches, etc.). Doctors were warned that heart patients should not be treated with nitroglycerin if the patient had used Sildenafil in the previous twenty-four hours. Additionally, the manufacturer reported several cases where patients who received both drugs died after developing irreversible hypotension (a severe drop in blood pressure).

Tadalafil has backache as its common side effect and also because of its long half life its not a drug which all men like.

A Safe Alternative 
As safety issues with PDE5 inhibitors, began to arise, researchers once again began to seek out safer alternatives for treating impotence. Many current pharmaceuticals have evolved from the historical search for herbal compounds to cure or reverse sexual dysfunction. Often, traditional nostrums rely on purely magical (placebo) effects, such as the phallic-influenced belief in the effect of rhinoceros horn—which, in fact, offers no benefit to humans and is fatal for the unfortunate rhino. Conversely, many plant-based traditional treatments, using herbs such as damiana, maca, muira puama, tribulus, and yohimbe, have been explored for their effectiveness in treating sexual dysfunction.

Need of the hour is a safe Neutraceutical  which justifies the male sexual response.

Male Sexual Response.

 

L-Arginine 
Viagra works to increase both the levels and activity of nitric oxide, leading to increased cGMP, increased blood flow to the genitals, and more intense sensations. Fortunately, there is a less expensive way to naturally increase the amount of nitric oxide released during sexual stimulation. The key is supplemental L-arginine, the direct precursor of nitric oxide.

In the 1990s, scientists discovered that L-arginine, a non-essential amino acid commonly found in the diet, is an oxidative precursor of nitric oxide (NO). As mentioned previously, nitric oxide is required for achieving and maintaining penile erection. Under conditions in which nitric oxide is produced for a specific physiologic purpose, the concentration of L-arginine (from which it is formed) can be a limiting factor.

 

A healthy sex life contributes to an improved quality of life and can have profound ramifications on emotional and physical well being. The compounds discussed here have been shown, singly and in combination, to be effective in supporting recovery from sexual dysfunction

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