University Of Alberta Researcher Offers Promising Treatment For Premature Ejaculation

A University of Alberta researcher has discovered a potential breakthrough for premature ejaculation--the most common sexual dysfunction in men--with a drug usually used to treat bi-polar or anxiety disorder.

Dr. Pierre Chue, a psychiatry professor at the U of A, has found success in treating premature ejaculation (PE) with the use of gabapentin, better known by the brand name Neurontin. Chue writes about his findings in the September issue of the "Canadian Journal of Psychiatry."

"This disorder affects almost 40 per cent of males--it is even more common than erectile dysfunction--yet it is not talked about much and there has been very little research on it," said Chue.

The essential feature of the disorder is persistent ejaculation with minimal sexual stimulation before or shortly after penetration and before the person wishes it. PE is believed to be a neurobiological phenomenon involving primarily a disturbance of serotonin receptor function. Currently, physicians prescribe medications that are known to influence these receptors--selective serotonin reuptake inhibitors or SSRIs--that delay ejaculation but these antidepressants also come with negative side-effects..

In his report, Chue cites a case study in which a 40-year-old man diagnosed with PE received minimal effectiveness from different techniques--the use of a condom with topical anesthetic and different antidepressant drugs--aimed to improve the disorder. The drugs resulted in such side effects as restless legs, headaches, decreased libido or accelerated ejaculation. The man "had previously found that alcohol produced satisfactory ejaculatory delay with no loss of erectile capacity, but clearly this was not a feasible regular option," says Chue. A trial of gabapentin taken one to two hours before intercourse proved effective. Higher doses prolonged ejaculation even further but also caused drowsiness.

Dr. Chue is not certain how gabapentin works to improve PE but believes it has to do with the drug's ability to increase aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the brain. Since there are currently no specific treatments for PE, the use of gabepentin to prolong ejaculation warrants further study, says Chue, particularly for those men where other therapies are ineffective or poorly tolerated.

Meanwhile, Chue is looking for people to participate in a clinical trial he is running that will use an SSRI-type drug called dapoxetine, to learn its effects on men with PE. This is an SSRI with a very short half-life that has been shown in clinical trials to delay ejaculation without the usual SSRI side effects.

Source: Science Daily

Erectile Dysfunction In Diabetic Men May Predict Silent Heart Disease

Men with type 2 diabetes who have difficulty achieving an erection could have heart disease and not realize it, according to a report in today's rapid access issue of Circulation: Journal of the American Heart Association.

Men who had silent, or symptomless, coronary artery disease (CAD) and type 2 diabetes were nine times as likely to have erectile dysfunction (ED) as were diabetic men who did not have silent heart disease.

"If our findings are confirmed, erectile dysfunction may become a potential marker to identify diabetic patients to screen for silent CAD," said lead researcher Carmine Gazzaruso, M.D., an internal medicine specialist at Maugeri Foundation Hospital in Pavia, Italy.

Erectile dysfunction and coronary atherosclerosis (narrowing of the coronary arteries) are frequent complications of diabetes, and the association between erectile dysfunction and overt or symptomatic CAD is well documented. However, many diabetic patients have asymptomatic (silent) CAD and are unaware of their heart disease risk. This is the first study to evaluate the prevalence of erectile dysfunction among men with type 2 diabetes and silent heart disease, researchers said.

"Silent CAD is a strong predictor of coronary events and early death, especially in diabetic patients," the investigators noted. "So, it is of interest to know clinical conditions associated with silent CAD to identify subjects who should be screened for CAD."

To evaluate potential associations between ED and silent coronary artery disease, the Italian group studied 133 men who had uncomplicated diabetes and silent coronary artery disease documented by coronary angiography, a test that produces images inside the heart's blood vessels. They were compared with 127 diabetic men who did not have silent heart disease, as verified by a series of tests.

Men in the two groups were evaluated for ED by means of the International Index of Erectile Function (IIEF), a widely used questionnaire to determine a man's ability to achieve erections. The IIEF was administered to all of the men as part of routine ED screening in the year prior to diagnosis or exclusion of silent CAD.

Diabetic men with and without silent CAD did not differ with respect to current forms of treatment. They also had similar rates of diabetic retinopathy, a diabetes complication that correlates with the severity of the disease.

Among the diabetic men with silent CAD, 33.8 percent had ED, compared to 4.7 percent of diabetic men who did not have silent CAD. A statistical analysis that evaluated potential risk factors for silent CAD showed that ED was a better predictor than more traditional risk factors for CAD. Risk factors for silent CAD were apolipoprotein(a) polymorphism (genetic alteration affecting cholesterol), smoking, microalbuminuria (protein loss related to kidney function), and levels of HDL (good) and LDL (bad) cholesterol.

The findings have several potential implications for the evaluation and management of diabetic patients, Gazzaruso said. First, erectile dysfunction warrants consideration with other CAD risk factors, such as high blood pressure and cholesterol abnormalities, in deciding whether a diabetic man requires more extensive evaluation for coronary artery disease.

A second implication relates to treatment of erectile dysfunction in diabetic men. The availability of oral medications for ED has raised questions about their use in men with cardiovascular disease, not only because the drugs can affect blood pressure, but also because they permit formerly impotent men with heart disease to resume sexual activity. Gazzaruso and his associates suggest that diabetic men with erectile dysfunction might require an exercise test or other evaluation for silent CAD before starting erectile dysfunction medication.

As for the possible biologic or physiologic mechanisms that link ED and silent CAD, the investigators cite microalbuminuria and neurologic disorders as possible explanations. However, they emphasize that more studies are needed to determine the precise nature of the association.

Source: Science Daily

Mayo Researchers Find Link Between Lower Urinary Tract Symptoms And Sexual Dysfunction In Older Men

Mayo Clinic researchers report in the latest issue of Mayo Clinic Proceedings that there may be an association between lower urinary tract symptoms and sexual dysfunction among older men. As the population ages, this finding will help further research that could help millions of men.

Lower urinary tract symptoms become common as men age and their prostates enlarge, restricting urine flow or altering their bladder habits. At this same age (age 65 and older) an estimated 100 million men worldwide experience erectile dysfunction. The Mayo Clinic researchers set out to determine whether the urinary tract symptoms and sexual dysfunction are related or not.

"This observation suggests there may be a common cause that someday may prove amenable to medical treatments that could be effective for treating both conditions," says Steven Jacobsen, M.D., Ph.D., a Mayo Clinic researcher and the senior author of the study in the June 2004 issue of Mayo Clinic Proceedings.

The researchers studied 2,115 male patients in The Olmsted County Study of Urinary Symptoms and Health Status Among Men. The men, ages 40 to 79, completed questionnaires in 1990 and were followed up every two years. Dr. Jacobsen says the study in Mayo Clinic Proceedings is one of the few community-based studies to assess the relationship between the symptoms of sexual dysfunction and lower urinary tract symptoms. In contrast, other studies examined only the association between individual urinary symptoms and sexual life dysfunction and lower urinary tract symptoms in selected patients who underwent medical or surgical treatments.

The symptoms that were most strongly associated with sexual dysfunction included a feeling of urgency, having to get up multiple times at night, a weak urine stream and straining to start urinating. These symptoms were all associated with difficulties with getting or maintaining erections, feeling of problems with sexual function and satisfaction. However, they were not strongly associated with sex drive after taking age differences into account.

Source: Science Daily

Smokers More Likely To Experience Impotence, Wake Forest Study Shows

Men with high blood pressure who smoke are 26 times more likely to have erectile dysfunction --impotence -- than nonsmokers, John Spangler, M.D., M.P.H., of Wake Forest University Baptist Medical Center told the American Society of Hypertension May 19 in San Francisco.

Erectile dysfunction, or impotence, is the inability of a man to achieve an erection or to complete intercourse, he said, and affects an estimated 30 million Americans.

"These data are the first to quantify a 26-fold increase in erectile dysfunction among primary care men with hypertension who also currently smoke, a rate that is also twice that of former smokers," said Spangler, associate professor of family and community medicine.

He said the study showed that former smokers among patients with high blood pressure are 11 times more likely to be impotent than non-smokers.

"Cigarette smoking, hypertension and erectile dysfunction are common disorders in primary care, and informing men who smoke of the exceptionally high possibility of developing erectile dysfunction may motivate many to quit their tobacco habit."

Spangler said that cigarette smoking and impotence had been linked previously by other investigators, including finding what doctors call a dose response relationship: the more cigarettes smoked per day the greater the chance of impotence.

But most of these earlier studies looked at a highly selective group of patients going to urology or cardiology clinics, he said. "This is the first study that looked at a primary care population and is more reflective of the general population."

Spangler said smoking has "both acute and chronic effects on erectile physiology." In both human and animal studies, smoking inhibits the ability to achieve a full erection.

Smoking also is known to accelerate atherosclerosis -- hardening of the arteries-- and when the blood vessels in the pelvis area are narrowed, that contributes to reduced penile blood flow.

"A smoking history should be obtained from all patients, especially those who report erectile dysfunction," Spangler recommended, "Informing men who smoke about the exceptionally high likelihood of developing erectile dysfunction should become a standard part of care of these patients." Spangler said the research team was surprised that there was no relationship between stress and impotence, but noted that the small size of the study -- 59 patients -- may have limited the chance to detect differences. The smoker versus nonsmoker difference, however, was dramatic.

"It may be that cigarette smoking and high blood pressure are such powerful risk factors for impotence that it just overshadows stress," he said.

The study was supported in part by a cooperative agreement from the Centers for Disease Control and Prevention. The team, in addition to Spangler, include John H. Summerson, M.S., Joseph C. Konen, M.D., M.S.P.H., and Ronny A. Bell, Ph.D. Konen is now at the Department of Family Medicine at Carolinas Medical Center in Charlotte.

Source: Science Daily

Study Pinpoints An Enzyme Key To Both Male And Female Sexual Dysfunction - Along With A Potential Treatment

Researchers at the University of Pennsylvania and other institutions have identified an enzyme that appears to play a key role in bringing on sexual dysfunction in both men and women – and a second molecule that can just as easily yank the offending enzyme out of commission. The findings, which carry the possibility of new treatments for sexual disorders, are scheduled to appear in two papers in the March 13 issue of Biochemistry, a peer-reviewed journal of the American Chemical Society, the world’s largest scientific society.

Led by Penn chemist David W. Christianson, the team found that the enzyme arginase can effectively short-circuit a biochemical pathway critical to male sexual arousal. But unlike remedies developed expressly for erectile dysfunction, which have proven disappointing in clinical trials with women, treatments that home in on arginase may offer hope for both sexes.

"There is intense interest in new targets for sexual dysfunction therapy," said Christianson, the Edmund and Louise Kahn Professor in the Natural Sciences. "Arginase should be a target in men and women alike, insofar as sexual dysfunction arises in both from circulation defects in the genitalia."

Offering the means to strike that target, Christianson and his co-authors pinpoint the amino acid derivative S-(2-boronoethyl)-L-cysteine, also known as BEC, as one of the tightest-binding arginase inhibitors ever identified. BEC joins another powerful arginase-blocking compound, (S)-2-amino-6-boronohexanoic acid, which was identified by Christianson in 1999.

In the chemical pathway that leads to sexual arousal in both sexes, arginase comes into play somewhat before phosphodiesterase V, the target molecule of Viagra – which could present a new solution for the roughly 3 in 10 men for whom that medication is ineffective. Viagra has shown even less success in preliminary studies of female sexual dysfunction.

Healthy sexual function in both genders relies on a biochemical cascade as carefully orchestrated as any courtship ritual. At one critical step in that pathway, nitric oxide synthase converts arginine, one of the 20 human amino acids, into citrulline and nitric oxide. The latter product is said to be the principal mediator of penile erection; it facilitates neurotransmission and causes rapid relaxation of smooth muscle in the penis’ spongy tissue, allowing the thousands of tiny vessels there to swell with blood.

Arginase can derail this reaction by sequestering arginine and breaking it down into compounds unrelated to those physiologically responsible for arousal, depriving the genitalia of the nitric oxide needed for sexual function.

"Both Viagra and BEC function by blocking enzymes that can degrade key chemical players in this pathway," Christianson said. "The difference is that Viagra works several steps later than arginase-inhibiting compounds."

Erectile dysfunction, which afflicts half of men older than 40 to some extent, occurs when this enzyme-mediated pathway goes awry, impeding blood flow in and out of the penis. Female sexual dysfunction can also result from impaired blood flow to the genitalia. Sexual difficulties in both genders often manifest themselves as side effects of heart disease, hypertension, diabetes and the use of certain medications such as antidepressants.

Working with tissue taken from men undergoing penile prosthetic implantation, Christianson and his colleagues verified for the first time that arginase is present in the human penis. The group also found that administering BEC enhanced smooth muscle relaxation in human penile tissue, which triggers erection by allowing the penis’ spongy tissue to fill with blood.

Christianson is corresponding author of the two Biochemistry papers. He was joined by J. David Cox, Ricky F. Baggio and Evis Cama of Penn and authors at Boston University, Temple University, the University of Pittsburgh, the Wistar Institute in Philadelphia and Université Paris. The work was supported by the National Institutes of Health.

Source: Science Daily

Beyond Viagra: Other Phosphodiesterase Inhibitors Are Candidates For Potential Therapies

The same basic process used by the popular pharmaceutical Viagra may someday help people suffering from a variety of conditions, from allergies to diabetes. Viagra’s success has raised interest in the growing study of phosphodiesterase (PDE) inhibitors, says Joseph Beavo, Ph.D., a professor of pharmacology at the University of Washington School of Medicine.

Viagra works by inhibiting one specific type of enzyme called a cyclic GMP phosphodiesterase. "There is not just one, but many phosphodiesterases. Different PDEs are expressed in different tissues and in different parts of the cell, and have different physiological functions. The challenge has been for the drug companies to find agents that are selective for specific phosphodiesterases so that they can treat the disease without causing toxic side effects," Beavo says.

Beavo discussed PDEs and their inhibitors during the "Signal Transduction" panel at the American Association for the Advancement of Science annual meeting here today.

The different PDEs make up a large class of enzymes. Beavo and his colleagues discovered many of the 11 families that are recognized so far. These enzymes are found throughout the body, where they modulate many important functions. For example, they play a key role in many sensory processes including vision and smell. They may even play a role in learning and memory. On the one hand, this means that drugs regulating PDEs may someday provide a treatment for people with vision or memory problems. But at the same time, any researcher wanting to use PDE inhibitors to treat one specific part of the body must make sure that the therapy does not interfere with other PDEs – such as the ones involved in vision or memory.

Most PDE inhibitors currently available as medication affect PDEs in multiple organs, and so their use is often limited by their toxic side effects. Viagra, introduced in 1999, became a poster child for PDE research in part because of its selectivity.

"Viagra was the first really successful PDE inhibitor, both mechanistically and commercially," Beavo says. Viagra has generated more than $1 billion in sales. It is among the most widely prescribed drugs.

Viagra is a very selective drug. It acts on one specific PDE found in the penis. In the presence of nitric oxide, a signaling molecule released from the nerves in the penis, inhibition of this PDE helps cause an erection.

Here is why inhibition of the PDE has that effect: nitric oxide causes the production of a secondary signaling chemical, cyclic GMP, which leads to erection. During sexual stimulation, men with erectile dysfunction may have trouble producing enough cGMP. Normally, the PDE breaks down the cGMP into molecules that cannot cause erection. By inhibiting the breakdown of cGMP, Viagra leads to more cGMP. In other words, PDEs cause reductions in the needed chemical in the penis, and Viagra blocks the PDE to prevent this from happening. Viagra generally does not have side effects caused by inhibition of other PDEs.

"We use Viagra's mechanism of action as a beautiful example of drug and physiological selectivity when we talk to students," Beavo says. Researchers are now seeking other PDE inhibitors that will also act selectively, without toxic side effects throughout the body. Since many PDEs have been discovered only within the past year, the search is just beginning.

Beavo’s lab recently characterized PDE7 and PDE8, which can be induced in certain kinds of immune cells -- particularly T-cells. These two families of PDE do not break down cGMP; instead, they reduce cAMP, a similar signaling molecule, found in those immune cells. Since these PDEs appear to be very important for immune system activity, researchers are studying whether inhibitors of these enzymes might have an effect on anti-immune and hyper-inflammatory diseases such as rheumatoid arthritis and allergies. Other PDEs are thought to mediate other processes. PDE3 affects insulin secretion (with potential involvement in diabetes) and leptin signaling (with dietary and fat implications). Researchers at drug companies and other universities are examining how PDE inhibitors may be used to improve memory, treat chronic obstructive pulmonary disease and blood clotting disorders. In all of these examples, considerable work and testing will be needed before there are clinical benefits, Beavo said.

Source: Science Daily

Study Appears To Suggest That Use Of Viagra May Have Adverse Cardiovascular Effects

A limited study conducted at Cedars-Sinai Medical Center in Los Angeles, and utilizing post-marketing adverse event reports made to the FDA, shows that there appears to be a high number of deaths and serious cardiovascular events associated with the use of Viagra, the most commonly prescribed therapy for erectile dysfunction in men. These findings will be presented March 14 at the meeting of the American College of Cardiologists in Anaheim, CA. Presenters will be Sanjay Kaul, M.D., and Babak Azarbal, M.D.

In an analysis of 1,473 major adverse events, 522 people died, the majority due to cardiovascular causes. According to the study's senior author, Dr. Kaul, the majority of deaths were associated with standard Viagra dosages (70 percent of the deaths were associated with the 50 mg dose), were due to cardiovascular causes and appeared to be clustered around the time of dosing (two thirds of deaths in which the time from ingestion to death was reported, occurred within 4-5 hours of taking Viagra). The majority of deaths occurred in patients who were less than 65 years of age, and who had no reported cardiac risk factors.

The study confirmed the well-documented increased risk with combined use of nitrates and Viagra. Of the 90 patients who were on nitrates and taking Viagra, death occurred in about 68 percent, and death or myocardial infarction occurred in 88 percent. However, the study showed that most deaths (88 percent) actually occurred in patients who were not taking nitrates, leading investigators to speculate whether there are some susceptible individuals who don't need nitrates to unmask the harmful effects of Viagra.

Source: Science Daily