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News in Brief

Bremelanotide: the female Viagra?

Pages 465-466 | Published online: 10 Jan 2014

An article in the Journal of Sexual Medicine recently reported the results of a Phase IIa clinical trial on the use of Bremelanotide, a first-in-class melanocortin agonist, in the treatment of premenopausal female sexual arousal disorder (FSAD).

Women aged 22–44 years of age diagnosed with the disorder received an intranasal 20 mg dose of the drug or placebo in one session and the alternate medication in a second session.

A measure of the patient’s vaginal pulse amplitude (VPA) was recorded both 20 min before and 60 min after dosing. Following a 24-h at-home period, the patients completed a questionnaire assessing their sexual activity and subjective evaluation of their desire and arousal.

The data indicated a positive correlation in the 24-h period between sexual desire and genital arousal in patients receiving bremelanotide, although there were no changes in VPA immediately following doses of the drug or placebo.

On the 14-item questionnaire, 67% of women reported an increased level of sexual desire after administration of bremelanotide, compared with only 22% of the placebo group. An increased level of genital arousal was reported in 72% of the bremelanotide-treated group. This was reported by 39% of the placebo group. Nausea and headache were the most commonly reported side effects.

Michael Perelman, Co-director of the Human Sexuality Program at Weill Medical College of Cornell University (New York, USA), feels optimistic that the data so far are encouraging and that the evaluation of bremelanotide should continue. ‘The potential use of this centrally acting compound to treat FSAD is the most interesting development in sexual medicine research in years. Once concluded, I look forward to reviewing data from the ongoing clinical trials.’

The results of the second part of the Phase IIa study are due to be released later in 2006. A Phase IIb clinical trial has also been initiated to asses 100 patients from 20 clinical sites across the USA. Its safety and efficacy in the treatment of male erectile dysfunction will also be investigated. Bremelanotide does not directly affect the vascular system like phosphodiesterase (PDE)-5 inhibitors. It also offers an alternative therapy for those patients who are contraindicated for or are nonresponsive to other drugs. Of those patients who receive an initial prescription of a PDE-5 inhibitor, 50% do not renew it owing to adverse events, ineffectiveness or drug interaction issues. These trials offer promising results in the development of a new drug to treat sexual dysfunction in men and women.

Chewing up a key regulator of fat synthesis keeps mice lean despite a high-fat diet

A novel pathway has been identified that regulates fat storage and metabolism in the body. Research by Scientists at the Salk Institute for Biological Studies (CA, USA) and published in Science showed that mice remained lean and were more sensitive to insulin despite a high-fat diet when the pathway was genetically modified to be overactive. This discovery could have important implications in the constant battle against obesity, diabetes and fat-related human diseases.

When humans have more fat in their diet through the consumption of foods, such as processed meat, fried food and sweets, they have an increased risk of fatty liver disease and obesity, which can lead to Type 2 diabetes. Marc Montminy, a professor in the Clayton Foundation Laboratories for Peptide Biology (CA, USA), reported that the genetically engineered mice were protected from fatty liver disease and did not gain weight, even when they consumed an equally high-fat diet.

The enzyme acetyl-coenzyme A carboxylase (ACC) allows the body to store fat. When humans fast, fat stores are burnt and ACC is phosphorylated and, therefore, made inactive. This study identified a protein called TRB3, which acts as a go-between for the degradation of ACC to ubiquitin, thereby reducing fat storage. This protein is normally only present in high quantities during fasting, when ACC is turned off, but keeping its production pathway turned on would enable TRB3 to degrade ACC whenever it is present and allow metabolism of fat depots. Recent findings from a team of Italian scientists have also linked TRB3 with high insulin levels and cholesterol, and cardiovascular disease, which further supports its role in the regulation of fat storage.

People with insulin resistance are at very high risk of developing Type 2 diabetes within 10 years unless they lose 5–7% of their body weight. This approach may be very important in future treatments of obesity and disorders characterized by insulin resistance, known as metabolic syndrome.

Fewer dietary restrictions for celiac sufferers

It is estimated that one in 200 people worldwide suffer an inherited inflammatory disorder of the small intestine called celiac sprue (celiac disease). New work reported in Chemistry and Biology reveal that an oral enzyme therapy may soon be able to combat the many symptoms of this disease.

Sufferers of celiac disease cannot tolerate gluten in their diet. If any is ingested, it sets off an inflammatory reaction that damages the small intestine leading to malabsorption, an autoimmune-like response, and many other complications. Celiac patients must use dietary therapy and exclude gluten from their diet. Gluten naturally occurs in grains, such as wheat, barley and rye. If trials of this new oral enzyme are good then a nondietary form of therapy would enable celiac patients to tolerate low-to-moderate levels of gluten.

Clever lateral thinking by researchers in Chaitan Khosla’s laboratory at Stanford University and Celiac Sprue Foundation (CA, USA) led to the hypothesis that if enzyme EP-B2 was taken from barley, where it normally digests gluten to provide energy during germination, it might digest gluten for celiac patients. Using recombinant bacteria to produce a form of EP-B2 that only activates under acidic conditions similar to the conditions found in the human stomach, the team demonstrated that EP-B2 efficiently digested gluten protein under gastric conditions. Critical to its potential as a therapy is the fact that EP-B2 was most specific for those parts of gluten that are known to trigger celiac pathogenesis.

Khosla’s team also reported on a second study in which they devised an even more potent double enzyme therapy for detoxifying gluten. EP-B2 was tested in combination with another well characterized enzyme called propyl endopeptidase (PEP). This is a powerful combination since EP-B2 breaks gluten proteins after glutamine residues, which comprise a third of all amino acid residues in gluten. PEP breaks gluten protein after proline residues, which are also abundant in inflammatory gluten peptides. The team showed that at very high gluten levels, where neither PEP nor EP-B2 alone could detoxify gluten quickly enough to prevent inflammation, a PEP and EP-B2 combination completely abolished gluten immunotoxicity within ten min under simulated gastric and duodenal conditions.

The power of this therapy resides in the role of EP-B2 initially cleaving gluten into small pieces under gastric conditions that were then easier for PEP to detoxify under duodenal conditions. This recombinant EP-B2 should be effective as a supportive therapy to help celiacs cope with avoiding gluten in everyday life. Considering how prevalent gluten is, this is clearly not an easy task. It is so widespread in foods that even patients on dietary exclusion treatment plans still present with structural and functional gut abnormalities since it is so difficult to exclude gluten. It is hoped that this work has paved the way for celiacs to resume a more normal diet in the future.

Calorie restriction beats exercise in the endeavor for longevity

It seems that if we want to live longer we need to eat less rather than exercise more, according to recent studies. While murine studies have demonstrated that both calorie restriction (CR) and exercise reduce the risk of diabetes, obesity, cardiovascular disease and some cancers, reducing energy intake is a key factor in promoting longevity, according to a study just published in the Journal of Clinical Endocrinology and Metabolism by Luigi Fontana, Assistant Professor of Medicine at Washington University in St. Louis (MI, USA) and an investigator at the Instituto Superiore di Sanita, Rome, Italy. Levels of the circulating inflammatory molecule tumor necrosis factor (TNF)-α are reduced in a low-calorie diet and a combination of this and lower thyroxin (T)3 concentration might slow the body’s aging process by reducing oxidative damage to cells and tissues, and the rate of metabolism. T3 controls body temperature, cellular metabolism and, to some extent, also appears to be involved with production of free radicals, unstable molecules that can damage cells. All are important aspects of aging and longevity.

Factors involved in primary aging determine the maximal length of life. Secondary aging refers to diseases that can prevent a person or an animal from reaching that expected lifespan. The present study indicates that a CR lifestyle may have a similar life-extending effect on humans as has been demonstrated in previous animal studies, which suggest that while leanness is a key factor in the prevention of age-associated disease, reducing caloric intake is necessary to slow down the inherent rate of aging. In fact, these studies showed that a CR lifestyle increased the animals’ maximum lifespan by up to 50%.

In the current study, 28 members of the CR Society were compared with two control groups who ate a standard Western diet, one of which also did endurance training. The CR group had been consuming approximately 1800 calories per day for an average of 6 years, although they still had the recommended daily amounts of protein and micronutrients in their diets. Data showed that T3 levels were only low in the CR group and there was no difference between the two study groups on a Western diet. Additionally, they had normal concentrations of T4 and thyroid-stimulating hormone and so were not at risk for clinical hypothyroidism.

Fontana’s group also reported recently that CR delays primary aging in the heart. Ultrasound studies showed that CR diets contribute to heart elasticity, which allows the muscles to relax between beats in a similar way to the hearts of younger people. Lower levels of T3, cholesterol and the inflammatory molecules TNF and C-reactive protein, combined with evidence of younger hearts in people on CR, suggest that humans on CR have similar adaptive responses to animals whose rates of aging were slowed by CR.

Future prospective studies include the Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy (CALERIE), which aims to measure inflammation, T3 levels, heart function and other markers of aging in normal-weight volunteers who have been on the CR diet for a year.

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