PD Patients Report Better Sleep With Rotigotine Tx

Patch form of dopamine agonist also lowered nighttime activity

SAN DIEGO -- The rotigotine patch (Neupro) appeared to objectively improve sleep quality in patients with Parkinson's disease with self-reported sleep complaints, Italian researchers said here.

Based on actigraph recordings, overall sleep efficiency was 67.8% in the week before treatment and 73.4% after 4 weeks of treatment with rotigotine patches for a statistically significant difference (P=0.017), according to Federica Provini, MD, of the University of Bologna, and colleagues.

In a poster presentation at Movement Disorders Society annual meeting, Provini's group noted that rotigotine is a dopamine agonist used for the treatment of motor symptoms in Parkinson's disease (PD) patients. Previous reports have suggested rotigotine use led to improvements in subjective sleep in PD patients with sleep complaints.

What was different in this pilot study was that the researchers used the actigraph, which records what really happens during sleep, to confirm the effectiveness of the patches.

"This is the first objective demonstration of rotigotine during sleep," said co-author Pietro Cortelli, MD, also at the University of Bologna. "Our study relied on the actigraph, not on questionnaires. The patients wore the actigraph 1 week before we treated, then we had the recording done after 4 weeks of treatment with rotigotine patches."

Cortelli told MedPage Today that the authors sought to show that the patches had an impact on the patient's sleep only. "We were not trying to determine if the patches improved motor function efficacy. We did not have a placebo group. We were just measuring their sleep efficiency," he said.

The patients were assessed using the Parkinson's Disease Sleep Scale, the Epworth Sleepiness Scale and the restless leg syndrome rating scale before the treatment. Their sleep was recorded with the actigraph to provide baseline data. The actigraph used was the Mini Motionlogger Actigraph Advanced by Ambulatory Monitoring.

Twelve of the 15 patients in the study were men and the mean age of all the participants was 67. They had been diagnosed with Parkinson's disease for a mean of 5 years. To be eligible for the study, the patients had to have registered sleep complaints and scored 10 or greater on the Parkinson's Disease Sleep Scale-2; a 3 or greater on the Hoehn and Yahr Score; and, prior to the study, could not have undergone treatment with rotigotine to control motor symptoms.

After 1 week without treatment, patients were treated with a 24-hour patch which was titrated over 1-4 weeks to the optimal dose to subjectively control motor symptom control. The starting patch contained 2 mg of rotigotine and the highest dose patch was 8 mg of rotigotine which was absorbed through the skin in 24 hours.

In addition to sleep efficiency, Provini told MedPage Today that there was a significant reduction in wake after sleep onset time (P=0.013). The wake after sleep onset time was 147.5 minutes in the week before using the patch and 106.5 minutes after the 1-month treatment trial, the researchers said. A longer wake after sleep onset is considered less efficient sleep quality.

The researcher also reported a reduction in the mean duration of wake episodes (P=0.005); improvement in the Unified Parkinson's Disease Rating Scale-III (P=0.018), and in the Parkinson's Disease Sleep Scale (P=0.005).

When looking at the patients who had pathological sleep efficiency pre-treatment, the authors reported a significant reduction in the nighttime activity mean (P=0.005) and activity median (P=0.04) post-treatment.

"This pilot study suggests that rotigotine subjectively improves sleep quality and [quality of life] in PD patients with self-eported sleep complaints and induces a significant reduction in nighttime activity, which could contribute to compromised sleep," the authors wrote, adding that in patients with reduced sleep efficiency, rotigotine objectively improved all sleep parameters.

Cortelli and Provini disclosed no relevant relationships with industry.

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Melanoma: Two Drug Combo Halves Death Risk

Progression, tumor growth slowed, side effects considerable but manageable

CHICAGO -- An immunotherapy combination for untreated melanoma reduced the risk of death or progression by more than half as compared with a drug currently used as a standard of care, a large randomized trial showed.

Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) had a median progression-free survival (PFS) of 11.5 months compared with 2.9 months for ipilimumab alone and 6.9 months with nivolumab monotherapy. Median PFS with the combination and with nivolumab alone increased to 14 months -- more than four times greater than the PFS of patients who received only ipilimumab -- among patients whose tumors tested positive for programmed death receptor ligand 1 (PD-L1), the target of nivolumab.

The PFS improvement came at a price of increased toxicity, as grade 3/4 adverse events occurred twice as often with the combination as with ipilimumab monotherapy, but even patients who discontinued treatment because of side effects did better with the combination, as reported here at the American Society of Clinical Oncology meeting."The majority of adverse events were managed and resolved with established algorithms, so based upon the available evidence, the combination represents a means to improve outcomes, particularly for patients whose tumors have less than 5% PD-L1 expression," Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, said during a press briefing.

The rationale for combining the two drugs comes from recognition that cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD-1 represent distinct but complementary pathways involved in the negative regulation of anti-tumor immunity. Ipilimumab targets CTLA-4 and nivolumab targets PD-L1. Preclinical and phase I and II clinical studies have consistently shown greater activity (including response, complete response, and survival) with the combination than with ipilimumab alone.

Wolchok reported findings from the first phase III trial to compare nivolumab alone or in combination with ipilimumab versus ipilimumab alone. Investigators in the multicenter trial enrolled almost 1,000 patients with untreated, unresectable, or metastatic melanoma. Patients were randomized to ipilimumab, nivolumab, or the combination. Treatment continued until disease progression or development of unacceptable toxicity.

Data were stratified by PD-L1 expression, BRAF expression, and melanoma stage (byAmerican Joint Commission on Cancer criteria). The trial had co-primary endpoints of PFS and overall survival, and Wolchok reported data for PFS. Secondary endpoints included objective response rate, correlation between PD-L1 expression and efficacy, and safety.

The primary comparison was nivolumab monotherapy and the combination versus ipilimumab alone, which is a current standard of care for the patient population enrolled in the study. The results showed that the combination reduced the hazard for death or progression by 58% versus ipilimumab alone (P<0.00001). Nivolumab alone reduced the hazard by 43% versus ipilimumab (P<0.00001).

An exploratory analysis showed that the combination significantly reduced the hazard for death or progression by 26% versus nivolumab monotherapy (HR 0.74, 95% CI 0.60-0.98).

The level of PD-L1 expression had a major influence on efficacy. Patients whose tumors had expression levels of at least 5% had median PFS of 14.0 months with the combination or nivolumab alone versus 3.9 months with ipilimumab. For tumors with PD-L1 expression <5%, the combination was the clear winner with a median PFS of 11.2 months compared with 5.3 months with nivolumab alone and 2.8 months with ipilimumab monotherapy.

Secondary analyses favored the combination and nivolumab over ipilimumab, including overall response rate (57.6% with the combination, 43.7% with nivolumab alone, and 19.0% with ipilimumab, P<0.001), complete response, and partial response. Median duration of response had yet to be reached in any of the treatment groups but favored the combination (13.1 months) and nivolumab (11.7) over ipilimumab (6.9).

Median reduction in tumor size was 51.9% with the combination, 34.5% with nivolumab, and 5.9% with ipilimumab.

On the basis of the efficacy analysis, the results appeared to be a slam-dunk for the combination. The safety data added a new consideration to the evaluation process.

In the combination arm, 55% of patients had grade 3/4 adverse events, most often diarrhea, elevated liver enzymes, colitis, rash, and fatigue. However, Wolchok emphasized that the rate was in line with earlier studies of the combination. Grade 3/4 adverse events occurred in 16.3% in the nivolumab arm and 27.3% of those treated with ipilimumab alone.

A similar difference existed across treatment groups with respect to the proportion of patients who discontinued because of grade 3/4 adverse events: 29.4% with the combination, 5.1% with nivolumab alone, and 13.2% with ipilimumab alone. However, patients who discontinued the combination had an overall response rate of 68%, and half of the responses occurred after patients stopped treatment, Wolchok said.

The trial had established guidelines for managing adverse effects and stopping treatment, and "clearly, they worked." Overall survival data, which continue to mature, should help inform discussions with patients about choosing between the combination and monotherapy, he added.

"This study highlights just how much progress we've made in the treatment of melanoma," said press briefing moderator Jyoti D. Patel, MD, of Northwestern University's Feinberg School of Medicine in Chicago. "Certainly, this is a powerful combination, and it comes with some toxicity, but it is clearly manageable in a global setting.

"The most important thing this study shows is that we are beginning to define which patients may benefit from one drug and those that may benefit from both drugs. That will only inform conversations about toxicity for patients and physicians as they decide the treatment course."

The study was supported by Bristol-Myers Squibb.

Wolchok disclosed relevant relationships with Bristol-Myers Squibb, Merck, Medimmune, ZIOPHARM Oncology, Polynoma, Polaris, Jounce Therapeutics, GlaxoSmithKline, Potenza Therapeutics, VesuviusPharmaceuticals, EMD Serono, Janssen Oncology, and Merck.

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New drug triggers tissue regeneration: Faster regrowth and healing of damaged tissues

Research focuses on select tissues injured through disease, surgery and transplants, but early findings indicate potential for broad applications

The concept sounds like the stuff of science fiction: take a pill, and new tissues grow to replace damaged ones. Researchers have now announced steps toward turning this idea into reality. They have detailed how a new drug repaired damage to the colon, liver and bone marrow in animal models -- even saving mice who would have died in a bone marrow transplantation model.

Scientist holding white laboratory mouse. (stock image)

Credit: © efmukel / Fotolia

The concept sounds like the stuff of science fiction: take a pill, and suddenly new tissues grow to replace damaged ones.

Researchers at Case Western Reserve and UT Southwestern Medical Center this week announced that they have taken significant steps toward turning this once-improbable idea into a vivid reality. In a study published in the June 12 edition of Science, they detail how a new drug repaired damage to the colon, liver and bone marrow in animal models -- even going so far as to save the lives of mice who otherwise would have died in a bone marrow transplantation model.

"We are very excited," said Sanford Markowitz, MD, PhD, the Ingalls Professor of Cancer Genetics at the university's School of Medicine and a medical oncologist at University Hospitals Case Medical Center's Seidman Cancer Center. "We have developed a drug that acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly. The drug heals damage in multiple tissues, which suggests to us that it may have applications in treating many diseases."

The institutions collaborating on this work next hope to develop the drug -- now known as "SW033291" -- for use in human patients. Because of the areas of initial success, they first would focus on individuals who are receiving bone marrow transplants, individuals with ulcerative colitis, and individuals having liver surgery. The goal for each is the same: to increase dramatically the chances of a more rapid and successful recovery.

The key to the drug's potential involves a molecule the body produces that is known as prostaglandin E2, or PGE2. It is well established that PGE2 supports proliferation of many types of tissue stem cells. Markowitz and University of Kentucky Professor Hsin-Hsiung Tai earlier had demonstrated that a gene product found in all humans, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), degrades and reduces the amount of PGE2 in the body.

Markowitz, also a Harrington Discovery Institute Scholar-Innovator, and James K.V. Willson, MD, a former Case Western Reserve colleague now at UT-Southwestern, hypothesized that inhibiting 15-PGDH would increase PGE2 in tissues. In so doing, it would promote and speed tissue healing. When experiments on mice genetically engineered to lack 15-PGDH proved them correct, the pair began searching for a way to inactivate 15-PGDH on a short-term basis.

The preliminary work began in test tubes. Yongyou Zhang, PhD, a Case Western Reserve research associate in Markowitz's lab and a lead author on the study, developed a test where cells glowed when 15-PGDH levels changed. Zhang then traveled to UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, where Willson serves as director. Zhang and UT Southwestern researchers Bruce Posner, PhD, and Joseph Ready, PhD, collaborated to comb through the center's library of 230,000 different chemicals. Ultimately they identified one chemical that they found inactivated 15-PGDH.

"The chemical, SW033291, acts in an incredibly potent way," Markowitz said. "It can inactivate 15-PGDH when added at one part in 10 billion into a reaction mixture, which means it has promise to work as a drug."

A series of experiments showed that SW033291 could inactivate 15-PGDH in a test tube and inside a cell, and, most importantly, when injected into animal models. The third finding came through collaboration between Markowitz and Stanton L. Gerson, MD, director of the Case Comprehensive Cancer Center, UH Seidman Cancer Center, and the National Center for Regenerative Medicine, as well as the Asa and Patricia Shiverick-Jane Shiverick (Tripp) Professor of Hematological Oncology.

Case Western Reserve research associate Amar Desai, PhD, worked between the Markowitz and Gerson laboratories to determine the effect of SW033291 on mice that had received lethal doses of radiation and then received a partial bone marrow transplant. Without SW033291, the animals died. With it, they recovered.

From there, more detailed studies showed that mice given SW033291 recovered normal blood counts six days faster than mice that were transplanted without receiving SW033291. In addition, SW033291-treated mice showed faster recovery of neutrophils, platelets and red blood cells. Neutrophils battle infection, platelets prevent bleeding, and red blood cells deliver oxygen throughout the body.

In addition, Desai's work showed that when SW033291 increases PGE2 in bone marrow, the body also begins to produce other materials that bone marrow stem cells need to survive. Finally, these benefits emerged without any adverse side effects, even at SW033291 doses much higher than would be required for 15-PGDH inhibition.

When investigators treated mice with other diseases, the SW033291 drug again accelerated tissue recovery. For example, the investigators teamed with Fabio Cominelli, MD, PhD, a Case Western Reserve Professor and Chief of the Division of Gastroenterology and Liver Disease, to study a mouse model of ulcerative colitis. SW033291 healed virtually all the ulcers in the animals' colons and prevented colitis symptoms. In mice where two-thirds of their livers had been removed surgically, SW033291 accelerated regrowth of new liver nearly twice as fast as normally happens without medication.

Because bone marrow, colon, and liver are significantly different tissues, the investigators believe the pathway by which SW033291 speeds tissue regeneration is likely to work as well for treating diseases of many other tissues of the body. However, the next stages of the research will concentrate on three diseases where SW033291 already shows promise to provide dramatic improvement.

In bone marrow transplants, for example, effects of SW033291 in accelerating tissue growth would provide the body the cells required to fight off the two most common and sometimes fatal complications, infection and bleeding. For those suffering the debilitating impact of colitis, accelerating tissue growth could heal colon ulcers more quickly, which in turn could allow patients to take lower dosages of other medications that treat colitis -- some of which have serious side effects. Finally, the promise of tissue growth could increase survival rates for patients with liver cancer; in some cases today, physicians are unable to perform surgery because the amount of the liver to be removed would be so great as to pose severe risk to the patient. But having a drug to accelerate the liver's regrowth could make surgery a viable option.

The team's next step will be to complete studies showing safety of SW033291-related compounds in larger animals, a required part of the pathway to secure approval from the U.S. Food and Drug Administration for trials in humans. If the drugs prove safe and effective in those clinical trials, they could then become available for general use by physicians. Investigators hope to partner with pharmaceutical companies to be able to start human trials within three years.

"These are thrilling times for us as researchers, and it is also an exciting time for Case Western Reserve," Markowitz said. "In Cleveland, there has been a major effort in the last two to three years to figure out how all our institutions can together work to develop drugs. This discovery is really something we should celebrate. It helps put us on the map as a place where new drugs get invented."

Markowitz added that this research received crucial financial assistance from Case Western Reserve University School of Medicine's Council to Advance Human Health (CAHH), from the Harrington Discovery Institute at University Hospitals, and from multiple National Institutes of Health grants that included the Case GI SPORE, led by Markowitz, and the National Center for Accelerating Innovation at the Cleveland Clinic. Additional support was received from the Marguerite Wilson Foundation; the Welch Foundation; the Cancer Prevention & Research Institute of Texas; Inje University; and the Korean National Research Foundation. Generous major gifts also came from the Leonard and Joan Horvitz Foundation and the Richard Horvitz and Erica Hartman-Horvitz Foundation.

Markowitz said the authors' contributions to this research are truly a tribute to the powers of collaboration. Senior authors Hsin-Hsiung Tai, Stanton L. Gerson, Joseph M. Ready, Bruce Posner, James K.V. Willson and Markowitz provided substantial leadership. Markowitz and Willson, former director of the Case Comprehensive Cancer Center and now director of the Simmons Cancer Center at UT Southwestern, initiated the project to study the potential of inhibiting 15-PGDH as a tissue-healing treatment strategy. Tai, at the University of Kentucky, Lexington, originally discovered 15-PGDH and tested SW033291 as a 15-PGDH inhibitor. Gerson and Markowitz partnered to show the SW033291 drug is effective for regenerating bone marrow in mice. Ready, a UT Southwestern chemist, synthesized SW033291 for the studies and has made multiple other highly promising derivatives of the compound. Posner, also a chemist from UT Southwestern, oversaw the search through the 230,000 compounds in the UT Southwestern chemical library.

Lead authors Yongyou Zhang, Amar Desai, Sung Yeun Yang, Ki Beom Bae, Monika I. Antczak, Stephen P. Fink and Shruiti Tiwari contributed equally to the scientific investigation. Zhang, Case Western Reserve, led the experiments that identified the drug. Desai, Case Western Reserve, performed experiments that showed that SW033291 works in bone marrow transplantation in mice. Yang and Bae, now at Inje University in Korea, worked in the Markowitz laboratory on studies of colitis (Yang) and on liver regrowth after surgery (Bae). Antczak worked in the Ready lab at UT Southwestern on the chemical synthesis of SW033291. Fink and Tiwari, both of Case Western Reserve, completed the work on the colitis mouse model.

Markowitz also cited important collaboration of two Case Western Reserve participating authors -- gastroenterologist Fabio Cominelli, who played a role in the success of the colitis experiments in mice, and Mark Chance, who contributed proteomics expertise for studies that showed how SW033291 works. Other participating investigators also contributed substantially: Joseph E. Willis, Dawn M. Dawson, David Wald, Wei-Dong Chen, Zhenghe Wang, Lakshmi Kasturi, Gretchen A. Larusch, Lucy He, Luca Di Martino, Juan Sanabria, Chris Dealwis, and Debra Mikkola, all of Case Western Reserve; Zora Djuric, University of Michigan, Ann Arbor; Ginger L. Milne, Vanderbilt University, Nashville; and Noelle S. Williams, Jacinth Naidoo, and Shuguang Wei, all at UT-Southwestern, Dallas.

"An impressive number of individuals contributed to the discovery of this 15-PGDH inhibitor drug," Markowitz said. "Each one of them has done something absolutely remarkable and indispensable to the success of the study."

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The above story is based on materials provided by Case Western Reserve University. Note: Materials may be edited for content and length.

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Body's response to spicy foods guides design of new pain relief drugs

The molecular interactions that allow capsaicin to activate the body's primary receptor for sensing heat and pain have been identified by scientists, paving the way for the design of more selective and effective drugs to relieve pain.

People sense ambient temperature changes.

Credit: Courtesy of J. Zheng lab

UC Davis researchers have identified the molecular interactions that allow capsaicin to activate the body's primary receptor for sensing heat and pain, paving the way for the design of more selective and effective drugs to relieve pain. Their study appeared online June 8 in the journal Nature Chemical Biology.

Capsaicin is the ingredient that makes chili peppers spicy and hot. The same pathway in the body that responds to spicy food is also activated after injury or when the immune system mounts an inflammatory response to bacteria, viruses, or in the case of autoimmune disease, the body's own tissues.

'While we have known that capsaicin binds to the TRPV1 receptor with exquisite potency and selectivity, we were missing important atomic-level details about exactly how the capsaicin molecule interacts with TRPV1, one of the body's primary receptors for sensing pain and heat,' said Jie Zheng, professor of physiology and membrane biology at UC Davis and senior author on the paper.

Using computer models based on atomic force fields and existing low resolution 3-D reconstructions of the TRPV1-capsaicin complex, the researchers identified several structural areas that enable capsaicin to strongly bind to the TRPV1 receptor.

'Computational biology methods are becoming very powerful tools for predicting and ultimately validating the high-resolution structure of important biological proteins and ligands, such as capsaicin and TRPV1, when they interact,' said Vladimir Yarov-Yarovoy, assistant professor of physiology and membrane biology at UC Davis and co-author on the study.

'These tools are especially useful when the interactions are small and transient, and cannot be captured easily with high-enough resolution using traditional experimental approaches,' he said.

Fan Yang, postdoctoral fellow in the Zheng lab at UC Davis and first author on the paper, agrees.

'The electron density observed in the cryo electron microscopy structure of the TRPV1-capsaicin complex is much smaller in size compared to the chemical structure of capsaicin,' Yang said. 'With computational docking, we were able to detail the atomic interactions between capsaicin and the TRPV1 channel and later validate the molecular architecture using other experimental approaches.'

The new structural information may serve to guide the drug-design process.

'Just as we can 'get used to' a spicy dish by the end of the meal, we believe that there are ways to develop highly specific molecules that make TRPV1 less sensitive to painful stimuli,' Zheng said.

The research also explains why capsaicin does not activate the body's other channels for sensing temperature, and why the TRPV1 receptor in many other species is not activated by capsaicin. For example, birds are missing two key interaction sites, which explains why birds are insensitive to the spiciness of chili peppers.

'It is thought that the presence of capsaicin is an evolutional advantage for plants, protecting them from species that would eat the leaves while allowing birds to ingest the peppers to spread the seed,' Zheng said.

The researchers also found that sweet peppers contain a compound called capsiate, which is almost identical to capsaicin in spicy peppers but differs at one key interaction site.

'The difference is sufficient to make the sweet pepper compound bind to TRPV1 very poorly, which is probably part of the reason why it does not taste spicy,' Zheng said. 'On the Scoville pungency scale, capsaicin is 16 million, and capsiate is only 16,000.'

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The above story is based on materials provided by University of California - Davis Health System. Note: Materials may be edited for content and length

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Will 'the female Viagra' really help women?

Later today, a committee of advisors to the Food and Drug Administration will vote on whether or not the agency should approve flibanserin - the much-hyped yet controversial "female Viagra." However, the drug has already been rejected twice previously by the organization, who cite safety concerns. In the wake of those decisions, battle lines have been drawn between those who feel the agency is discriminating against the sexual health of women and those who feel the language of sexual equality has been hijacked in an attempt to force an ineffective and unsafe drug on the market. We take a look at both sides of this dramatic debate.

Campaigners for flibanserin claim that 26 drugs have been FDA-approved for male sexual dysfunction and none for women.

480 was not a viable angina treatment, Pfizer took an interest instead in its unintended effects. As a treatment for erectile dysfunction, UK-92480 was much more effective than a placebo. In 1998, the drug was approved for this use by the Food and Drug Administration (FDA), and it was rechristened Viagra.

In the 17 years since, drugs acting as variations on Viagra's mechanism have also made it to market as erectile dysfunction treatments. What has been conspicuous in its absence, however, has been "a Viagra for women."

Following the FDA's second decision not to approve flibanserin, in fall 2014, two well-funded media campaigns - Even The Score and Women Deserve - set about engaging women's groups, starting up petitions and lobbying policymakers on the issue. A mantra of these campaigns is the figure "26-0."

What 26-0 relates to is a claim made by Cindy Whitehead, the CEO of Sprout Pharmaceuticals (who now own flibanserin) - and reportedly the creative mind behind Even The Score and Women Deserve - that 26 drugs have been FDA-approved for male sexual dysfunction and none for women.

Watch Women Deserve's Viagra parody video below:

"Women have waited long enough," write Even The Score, of their pro-flibanserin petition, which is reported to have attracted more than 40,000 signatures. "In 2015, gender equality should be the standard when it comes to access to treatments for sexual dysfunction."

Accusations of data manipulation

However, critics have claimed that Even The Score's campaign is built on misinformation. The 26 products for male sexual dysfunction are actually different regional brands of the four main erectile dysfunction treatments, which themselves adhere to a similar mechanism.

Do 43% of American women really have a sexual dysfunction?

Another statistic wielded by the campaigns - the claim that 43% of American women have a sexual dysfunction - has also come under fire. The figure is drawn from a contentious 1994 survey that gave its female respondents the option of answering yes or no to whether they had any sort of sexual problem, but the survey did not collect any data on what the nature of the problem was - even the senior author of that study has reportedly claimed the statistic is misused.

A claim published on womendeserve.org that "a biological lack of desire to have sex negatively impacts 1 in 10 American women" was questioned in a high-profile LA Times piece by Kinsey Institute research fellow and sexologist Prof. Ellen Laan, and Leonore Tiefer, professor of psychiatry at NYU School of Medicine and founder of the New View Campaign.

"No diagnostic test has identified any biological cause - brain, hormone, genital blood flow - for most women's sexual problems," the pair wrote. Rather, they claim that low sexual desire in women more likely reflects a difference in desire between the two partners.

"It is unethical and unscientific to attribute a couple's discrepancy in desire to the woman's biological deficit," they continue, pointing out that studies have shown women's response to both test medications and placebo drugs is high. "These repeated findings do not support the 'unmet medical need' theory."

What Laan and Tiefer's article and the New View Campaign emphasize is that Viagra and flibanserin are false equivalents. Viagra treats erectile dysfunction, while Sprout claim that flibanserin is an antidote for low sexual desire in women. Viagra does not increase male libido; rather it acts on the mechanism that allows an erection to happen.

What flibanserin is concerned with - boosting sexual desire - is more amorphous and complex. New View even argue that male and female sexual dysfunctions are also not equivalents, so a female Viagra would therefore not be appropriate for women.

'Hypoactive sexual desire disorder' and the DSM

The New View Campaign take issue with the current sexual dysfunction classification implemented by the American Psychiatric Association (APA) in its 1980 edition of the Diagnostic and Statistical Manual of Disorders (DSM), which envisions male and sexual "dysfunction" as equivalents across four categories: sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders.

The illness that flibanserin is purported to treat - hypoactive sexual desire disorder - was removed from the DSM in 2013.

They consider that this has led to a reductive, mechanistic perception of how female sexuality works in relation to male sexuality. They argue that women's sexual problems are less physiological and genital-focused than men's, that "women generally do not separate 'desire' from 'arousal,' women care less about physical than subjective arousal, and women's sexual complaints frequently focus on 'difficulties' that are absent from the DSM."

"The DSM takes an exclusively individual approach to sex, and assumes that if the sexual parts work, there is no problem; and if the parts don't work, there is a problem," summarize the campaigners.

Instead, the campaigners say, it has fostered a commercial drive to produce "a female Viagra" - a pharma sensation that will repeat the massive success of that drug for a new audience, regardless of whether pharmacology is the correct intervention, or to what extent there is a problem that requires treatment.

In fact, the specific illness that Sprout argue flibanserin treats - hypoactive sexual desire disorder (HSDD) - was removed from the DSM in 2013.

Medical News Today spoke to Thea Cacchioni, an assistant professor of women's studies at the University of Victoria in British Columbia, who testified against flibanserin the first time it was unsuccessfully submitted for FDA approval in 2010. She asserted bluntly of flibanserin's position in the modern pharmaceutical landscape: "there is no recognized illness it treats."

"There are many problems with the HSDD disorder, as I mentioned in the hearing," Cacchioni told us, "how could we ever come up with a baseline level of normal desire? Norms of desire vary from era to era and culture to culture. Also, research shows that most desire problems are caused by external factors - interpersonal, relationship issues, social judgements and pressures related to especially women's sexuality, feelings of inadequacy, work stress, etc."

As fascinating as the cases for and against the idea of a pharmaceutical intervention for female sexual dysfunction are, the issues that Cacchioni and others expressed the greatest concern about when testifying in 2010 were much less philosophical and more to do with hard data.

Does flibanserin work and is it safe?

Firstly, does flibanserin work? The evidence presented to the FDA was perceived as being somewhat subjective - clinical trial found that it produced an additional 0.7 "sexually satisfying events" per month.

Secondly, is flibanserin safe? The drug's clinical trials saw a 14% drop-out rate due to adverse effects. The full data were not reported on what these adverse effects were, but what is known is that women taking flibanserin had 10 times the risk of dizziness and four times the risk of sleepiness compared with a control group.

"These may sound minor," explained Cacchioni, "but since this drug was tested on a highly select group of women, there is concern over what would happen if a wide population of women take this drug on a daily basis? What drug interactions will we see? Is there a risk of impaired driving?"

Whether or not Sprout will be "third-time lucky" in today's quest for FDA approval hinges on new evidence the agency has requested the pharma company submit regarding the possibility of impaired driving.

Cacchioni, who has also written a book on the issue - "Big Pharma, Women, and the Labour of Love," out in August - is not convinced the new data will be enough to swing an FDA approval, despite the intense media attention and public interest the case has received.

"Clearly, Sprout is hiding something," she told us, "since they have followed up on this important request by submitting evidence from only 25 volunteer participants, 23 of whom are men! They claim they could not find any more women who were moderate drinkers."

She adds:

"I have faith that the FDA will stand its ground and not approve flibanserin. If they do, they are sending a very dangerous message - that drug companies and their marketing machines can pressure them into approving drugs that are unsafe and ineffective."

In a recent blog for Science 2.0, Josh Bloom - director of chemical and pharmaceutical sciences at The American Council on Science and Health in New York City, NY - says that while the statistical significance of improvement in sexual arousal was excellent in flibanserin's trial, a "statistically significant improvement in a study is not the same as a significant clinical improvement." He elaborates that, in terms of evidence of improvement, "there are no 10-fold differences as was the case with adverse effects. The differences in efficacy are roughly in the 1.5-fold range."

"Which brings up the exact same question that the FDA is faced with every time it decides whether a drug gets approved or not," Bloom writes. "Do the benefits outweigh the risks? The FDA has already said no three times. This should have been over with long ago."

So why are Sprout persisting with flibanserin? The company was founded in 2011 by Cindy and Robert Whitehead, who raised $50 million to save the drug from the scrapheap, after it was first declined by the FDA.

The drug's creators, the German pharma company Boehringer Ingelheim, gave up on flibanserin. Like Viagra, the drug was not developed to be a treatment for sexual dysfunction - it was a prospective antidepressant. Antidepressants that increase serotonin have a side effect of dampening sexual response. However, flibanserin seemed to improve it - possibly by raising the levels of the neurotransmitters dopamine and norepinephrine while decreasing serotonin.

Flibanserin as sexual equality battlefield

Sprout, via the Even The Score and Women Deserve campaigns - coordinated with the largely big pharma-funded International Society for the Study of Women's Sexual Health - have painted the battle to get flibanserin to market as an ideological struggle against a patriarchal and discriminatory regulatory system that is not fit for meeting the health needs of women.

Despite support from the National Council of Women's Organizations, the Black Women's Health Imperative, Jewish Women International and the Association of Reproductive Health Professionals, the emotive pro-flibanserin campaign has not washed with everyone. Ellen Laan and Leonore Tiefer were scathing in their dismissal of its rhetoric:

"As professional sexologists and advocates of women's sexual rights, we were horrified by the campaigns' use and abuse of the language of equality to pressure the FDA to approve a potential billion-dollar blockbuster 'pink Viagra.' The only two drugs for women's sexual dysfunctions that have come to the FDA in the 16 years since Viagra was approved were rejected. [...] The drugs for women didn't work and were unsafe. Not approving them isn't sexism, it's proper regulation."

Cacchioni concurs, suggesting that perhaps the reason why no drugs have been shown to be safe or effective "is that most sexual problems are related to interpersonal, psychological, and social factors, including the social construction of sexual norms."

"Perhaps," she concludes, "we are putting too much pressure on ourselves to realize a level of desire that is not realistic for everyone across the life course."

With several FDA rejections and $50 million of investment already behind them, it will be interesting to see how Sprout and Even The Score will continue to frame the debate for "a female Viagra" if approval today is not forthcoming.

If it does succeed in winning approval, however, the Whiteheads could have a blockbuster drug on their hands with a market value of billions.

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Drop in abuse and overdose after opioids were made crush-resistant

After 2010, when oxycodone - a high-dose opioid painkiller sold as OxyContin - was switched by its manufacturer to a new abuse-deterrent formulation, overdose rates fell substantially, researchers have found.

In addition to potential misuse by people receiving the original prescription, opioid painkillers may be diverted to illicit users.

The formulation change also saw a drop in the levels of dispensing, and the lower opioid overdose and prescribing levels also correlated with the withdrawal from the market of another narcotic drug in the same year, propoxyphene.

OxyContin is an extended-release formulation to deliver its higher painkilling dose in a more controlled way, but misuse of this opioid for a quicker "high" had been possible by crushing or dissolving the medication to bypass this design. The new formulation, however, is resistant to this abuse strategy.

Propoxyphene (Darvon) was withdrawn from the US market in 2010 because of data about its cardiac side-effects. First approved for sale as an analgesic in 1957, it soon became prone to misuse - and the authors cite that, by 1977, propoxyphene was the "second-leading agent in prescription drug-induced deaths."

The authors of the study in JAMA Internal Medicine describe the reduction in dispensing following these two pharmaceutical industry changes in 2010:

"The introduction of abuse-deterrent OxyContin and withdrawal of propoxyphene at the end of 2010 were associated with sudden, substantial and sustained decreases in prescription opioid dispensing.

The estimated decrease in opioid dispensing at 2 years would be enough to supply 5 mg of oxycodone each day of the fourth quarter of 2012 to 5% of the population."

Fall in level of morphine-equivalent amounts dispensed

The researchers analyzed the prescribing of opioids to commercial health plan members across the US to reach the estimated average level of morphine-equivalent dose (MED).

For all opioids combined, between 2003 and the third quarter of 2010, the dispensing rate rose from 95 mg to 163 mg MED per plan beneficiary.

Immediately following the interventions, the dispensing rate dropped by 14.8 mg MED per member, and a downward trend then continued to buck predictions, leading to the rate in the last quarter of 2012 being estimated at 139 mg MED per member, down from the 163 mg peak.

Against the predicted trend of opioid prescriptions, this represented a 19% decrease following the 2010 changes. Further, the estimated rate of overdose also dropped - by 20%.

The prescribing data, drawn from over 31 million insured members, were analyzed by Dr. Marc Larochelle, of the Harvard Medical School and Boston University School of Medicine, and coauthors. They conclude:

"Our results have significant implications for policymakers and health care professionals grappling with the epidemic of opioid abuse and overdose. Changes imposed through regulatory mandates or voluntary company actions may be a viable approach to stemming prescription abuse."

A note of caution is made with this call, however, to reduce opioid supply without harming access to the therapeutic benefit of painkilling treatments.

The authors also warn that interventions at the supply end do not cure the present demand problem, even though it "might decrease new-onset addiction in the future."

Alongside the opioid findings, the authors found that heroin overdose, conversely, increased by 23% in the study period. The authors note:

"Regardless of the mediating mechanism, a transition from prescription opioid to heroin abuse has been well documented and further efforts are needed to improve identification and treatment of these individuals."

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