Parkinson’s Medications May Cause Premature Ejaculation, Case Report Suggests

premature ejaculation

Antiparkinsonian medications may cause premature ejaculation in men with Parkinson’s, according to a case series that followed eight patients.

The study, “Acquired premature ejaculation in Parkinson’s disease and possible mechanisms,” was published in the International Journal of Impotence Research.

Premature ejaculation is a common male sexual dysfunction and can be a source of significant distress in men and their partners.

This dysfunction can be classified into lifelong premature ejaculation (LPE) and acquired, or secondary, premature ejaculation (APE). While with LPE, patients experience early ejaculation independent of sexual partners and starting in their first sexual encounters, those with APE develop early ejaculation after having previous normal ejaculation experiences.

Information on the prevalence of LPE and APE is scarce, and patient self-reports often conflict with clinician diagnosis.

Among the main causes of APE are sexual performance anxiety, psychological or relationship problems, and erectile dysfunction, as well as medical causes such as hyperthyroidism and prostatitis, or prostate inflammation.

Compared with men with LPE, those with APE are typically older, have a higher body mass index, and also have a greater incidence of hypertension and diabetes mellitus, among other conditions.

Sexual dysfunction is common in men with Parkinson’s, affecting 40.6-51.5 percent of them; however, these issues have not been studied in detail. Erectile dysfunction and premature ejaculation are the predominant forms of sexual dysfunction in this patient population.

The case series described eight men followed between 2008 and 2014 who attended a sex therapy specialist due to a new onset of premature ejaculation.

Patients’ mean age at Parkinson’s onset was 57.3 years and 62.6 years at study inclusion. Half had normal ejaculatory function before Parkinson’s diagnosis, while the remaining four experienced ejaculation within two to three minutes, though not regarded as problematic.

All patients reported a significant reduction in intravaginal ejaculation latency time (the time taken for a man to ejaculate during vaginal penetration) after Parkinson’s diagnosis.

Three patients experienced severe premature ejaculation, meaning that ejaculation occurred before penetration, while four reported ejaculation immediately following vaginal penetration. In addition, erectile dysfunction and/or altered sexual desire occurred in some of the patients.

Of note, all patients were taking anti-parkinsonian medications at premature ejaculation onset, including levodopa in two patients, dopamine agonist in three, and both in one patient. Azilect (rasagiline), amantadine, and an anticholinergic medication were also used.

Psychiatric medications included amitriptyline, Remeron (mirtazapine), and Zyprexa (olanzapine), taken by three patients. Four patients had hypertension, while ischemic heart disease, diabetes mellitus, hyperlipidemia (high cholesterol), benign prostate hypertrophy (enlarged prostate gland), and chronic heart failure were also reported.

“In this case series of [Parkinson’s] patients with APE, the ejaculatory dysfunction developed when patients were on antiparkinsonian medications, suggesting a possible medication effect,” the researchers wrote.

However, since premature ejaculation appeared a mean of four years after Parkinson’s onset, the authors also suggested that Parkinson’s progression may be an additional cause of premature ejaculation.

“Further research with a larger cohort is required on premature ejaculation in the constellation of Parkinson’s disease with a focus on the impact of Parkinson’s disease medications on the onset of premature ejaculation and the effect of anti-parkinsonian medication adjustment, as well as effects of available medications for premature ejaculation on the severity of this disorder,” the authors concluded.

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#AAN2018- Inbrija Reduces Parkinson’s Off Periods, Phase 3 Trial Shows

Phase 3 Inbrija trial

Inbrija reduces Parkinson’s symptoms when standard treatments wear off, and decreases the length of these off periods, a Phase 3 clinical trial shows.

The therapy’s developer, Acorda Therapeutics, will present the results at the American Academy of Neurology annual meeting in Los Angeles, April 21-27. Parkinson’s News Today will be covering the conference.

Acorda’s presentation will be at 4:54 p.m. Pacific time on Tuesday, April 24. The title will be “Long-term Efficacy of Inhaled Levodopa in Parkinson’s Disease Subjects With Motor Fluctuations: a Phase 3 Open-Label Randomized Study.”

Inbrija (CVT-301) is a self-administered, inhaled version of levodopa intended to reduce the time when standard levodopa treatment wears off — periods known as off times.

Acorda conducted the Phase 3 trial (NCT02352363) to evaluate the safety and effectiveness of an 84-mg dose of Inbrija over 12 months in 408 Parkinson’s patients with movement problems.

The Inbrija group consisted of 278 patients. The other 130 were assigned to standard care. Only 204 of the patients who received Inbrija were able to complete the trial.

At the beginning of the study, the Inbrija group had a mean age of 63.6 years, had had Parkinson’s for nine years, were averaging 3.6 off periods a day, and were experiencing total off times of 5.6 hours per day. Patients took an average of 2.3 doses of Inbrija a day.

One of the measures that researchers used to measure Inbrija’s effectiveness was improvements in patients’ UPDRS-III scores, which assess both movement and non-movement symptoms, 10, 20, 30, and 60 minutes after dosing. Another measure was the percentage of patients able to regain control of their symptoms within 60 minutes of treatment.

Still another measure was reductions in patients’ off times. And a fourth was better scores on a scale known as PGIC, which shows whether a patient believes a treatment is effective.

A key finding was improvements in Parkinson’s symptoms at all time points between week 4 and 52 on the UPDRS-III scale.

Another finding was that patients were able to regain control of their symptoms within 60 minutes.

In addition, patients were able to reduced their total daily off times by between 1.32 and 1.42 hours. And 75 percent of patients showed improvements in PGIC scores.

Overall, improvements in UPDRS-III scores, daily off times and PGIC scores “support the efficacy of up to 52 weeks of treatment with CVT-301 (Inbrija) 84 mg in the treatment of off period symptoms,” the researchers wrote.

The results prompted Acorda to seek European Union approval of Inbrija as a treatment for off periods in Parkinson’s.

In addition to data from this Phase 3 trial, Acorda’s application to the EU included results of the Phase 3 SPAN-PD trial (NCT02240030) in 351 participants and the Phase 3 CVT-301-004E trial (NCT02242487) in 325 participants.

The U.S. Food and Drug Administration accepted Acorda’s New Drug Application for Inbrija in February 2018. It is expected to decide whether to approve it by October 5.

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Acorda Campaign Aims to Help Parkinson’s Patients Explain Their Challenges

Steve DeWitte

An initiative called Live Well. Do Tell is trying to help Parkinson’s patients do a better job of letting others know about the manifestations of their disease, particularly the return of movement problems during periods when standard treatments wear off.
In addition to these off periods, many people are unaware of the non-movement symptoms of Parkinson’s, including depression or anxiety.
One feature of the Acorda Therapeutics initiative is a downloadable action guide designed to help patients and caregivers do better at identifying and communicating symptoms.  The guide grew out of a meeting of patients, healthcare professionals and others on Sept. 17, 2017. The main thrust of the gathering was finding ways of both addressing the disease’s  challenges and letting others know about them.
Suggestions included broadening people’s understanding of off periods, helping caregivers  do a better job of describing the symptoms they are seeing to healthcare professionals, and coming up with a better way of measuring off periods.

“This disease can be a hard disease, but there’s a whole lot of hope right now, too, because of a growing understanding of how it manifests,” said Sarah Jones, chief executive of the Parkinson & Movement Disorder Alliance, and a member of the initiative’s steering committee. “This group balances truth-telling with power. Information is power, along with knowing what to do with it.”

Others are invited to join the conversation by signing up for initiative updates and news.

Parkinson’s is a progressive neurodegenerative disorder that predominately affects dopamine-producing nerve cells in an area of the brain called substantia nigra. Experts estimate that it affects a million people in the U.S. and 10 million worldwide.

Because of the variety of symptoms, patients usually see a number of specialists over the course of their disease, including neurologists and movement-disorder experts.

Matthew Stern
Dr. Matthew Stern, a neurologist, was chair of the Live Well. Do Tell steering committee. (Photos courtesy of Acorda Therapeutics)

Too often, physicians focus on visible symptoms such as tremors, slow or jerky movements, limb rigidity, and walking and balance problems, said Matthew Stern, a professor emeritus of neurology at the University of Pennsylvania’s Perelman School of Medicine. Meanwhile, doctors often focus on depression and constipation in  judging quality of life. Stern was chair of the Live Well. Do Tell steering committee.

“It’s no longer about just walking into an exam room. It’s about you taking control of your own health care,” said Stern, former director of the Penn Parkinson’s Disease and Movement Disorders Center. “But a byproduct will be increased doctor awareness as well. There’s a disconnect between what a patient is saying and what the doctor is hearing.”

Although off times can cause movement problems and complications such as difficulty swallowing, they also can lead to bouts of anxiety and sadness — less-evident symptoms that often go undiagnosed. Up to 80 percent of Parkinson’s patients experience off times daily, Jones said.

Because movement and other difficulties return during off times, patients can find it hard or embarrassing to discuss these periods. Often, they aren’t sure how to explain what they feel about them.

“The complications of off times really lend themselves to misunderstandings, and can also really overwhelm people dealing with the disease,” Jones said. “This organization raises a voice in terms of understanding what off time is, and the fact that it varies.”

These periods can also leave patients with feelings of inadequacy or failure. “They feel like they aren’t managing as well as they want to,” Jones said. “It can be tied to stress or not sleeping well. So, normalizing it is very helpful. If there’s no way to talk about it, it can be seen as a criticism or can create challenges, as opposed to being a part of living.”

Options for managing off times include diet and medication adjustments and, for some, surgical approaches such as implanting deep brain stimulation devices.

Acorda has asked the U.S. Food and Drug Administration to approve a treatment it developed for off times. Inbrija is an inhaled powder formulation of levodopa designed to act quickly when the effects of oral levodopa and carbidopa wear off.

The FDA is expected to decide whether to approve inbrija by Oct. 5. Acorda’s application for approval was based partly on the benefits seen in a Phase 3 clinical trial (NCT02240030).

“Off periods greatly disrupt the lives of people living with Parkinson’s, and there is significant need for new treatments in this community,” Dr. Burkhard Blank, Acorda’s chief medical officer, said in a press release.

Most Parkinson’s patients are diagnosed between the ages of 55 and 60 while still employed, leading to panic and fear. That’s when doctors need to reassure them, Stern said.

“Patients think they’ll be in a wheelchair in five years,” he said. “So, step one is educating a diagnosis. When I was in clinical practice, I spent a lot of time undoing what they’re told and what they’ve learned on the internet.”

Steve DeWitte of Connecticut had no idea of “how to react” when diagnosed with Parkinson’s in 2005.

Steve DeWitte was 48 and a Special Olympics regional director when he received his diagnosis. Two years earlier, his symptoms had begun with a shaky left pinky finger. The tremors spread to more fingers and then his entire left arm. He eventually also had bouts of fatigue, sleeping difficulties and constipation.

“I didn’t know what Parkinson’s was, so I didn’t know how to react or not react,” said DeWitte, a resident of New Preston, Connecticut, who founded Connecticut Advocates for Parkinson’s. “Then I said, ‘OK, I’ll accept it.’ After that, I did my own research and joined support groups to find out what steps I had to take to live a quality life.”

Now 61, DeWitte said how he feels about his situation can change hourly. Overall, he said, he is able to manage his disease, including off times, with medicine, diet and exercise. He’s been involved with the Live Well. Do Tell effort from the beginning.

“It’s a great program for individuals as they start examining how to live with Parkinson’s, and how doctors can better communicate with you,” said DeWitte, who is married and has an adult child. “I give my interpretation of how we’re living with this condition, how we talk to physicians and how they listen, and how they can be more clear with us.”

He thinks the initiative has helped create a more honest dialogue between patients and physicians. “Patients feel more comfortable coming out with what they experience,” he said. “We’ve had wonderful sessions leading us through how to prepare for our visits, and getting helpful hints about how to make each visit more impactful. It makes it easier on the physicians, too.”

Insights into these sessions are available for downloading.

Jones said the bottom line with Live Well. Do Tell is that it challenges everyone in the Parkinson’s community to do a better job at explaining the disease and its symptoms, and it challenges patients to advocate for themselves.

“It feels like this is the first time that a large organization has pulled together a really diverse multidisciplinary team of people to have a conversation about more than motor symptoms,” she said.

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Voyager’s Gene Therapy Improves Parkinson’s Patients’ Movement Over Long Term, Trial Shows

Long-term Parkinson's trial

A single administration of Voyager Therapeutics gene therapy improves advanced Parkinson’s patients’ movement up to three years later, a Phase 1b trial indicates.

Voyager designed VY-AADC01 to deliver the aromatic L-amino acid decarboxylase (AADC) gene to a specific brain region, the putamen. The gene provides instructions for the production of the AADC enzyme. The enzyme is responsible for converting the treatment levodopa into dopamine, the signaling molecule that is missing in Parkinson’s patients.

In advanced Parkinson’s disease, AADC expression is lowered. This leads to the death of nerve cells that produce dopamine in the substantia nigra — a midbrain region. The neuron deaths prevent the substantia nigra from being able to convert oral levodopa to dopamine.

Voyager’s gene therapy is aimed at increasing dopamine production in the putamen, bypassing the effects of the dying dopamine neurons. The goal is for the treatment to improve motor function while reducing the requirement for levodopa or other dopaminergic medications.

VY-AADC01 is being evaluated in both the Phase 1b (NCT01973543) trial and a Phase 1 study (NCT03065192) in patients with advanced Parkinson’s.

Previous data had shown that a single treatment triggers a dose-dependent and time-dependent response across multiple measures of motor function. It also increased AADC enzyme activity and enhanced levodopa’s response.

The Phase 1b trial data that Voyager just announced showed that the therapy continues to yield robust and durable improvements in patients’ motor function from a year to three years later. It also allowed patients to make substantial reductions in their use of daily oral levodopa and other Parkinson’s medications.

The trial includes 15 patients with advanced Parkinson’s disease who have disabling motor fluctuations despite treatment with optimal anti-Parkinson’s medications. Patients are 58 years of age on average and have had a Parkinson’s diagnosis for 10 years.

Key trial objectives are to assess the efficacy of three increasing doses of VY-AADC01 given in a single administration, and to see if the treatment is safe and tolerable.

Among the three groups of patients, those who received the second-highest dose have achieved the best results. They experienced the highest improvement in daily levodopa on-time without any impairment of voluntary movement.

During the trial, patients were instructed to reduce their daily doses of oral levodopa and related medications­­ — called levodopa equivalent doses — to achieve optimal motor control after treatment with VY-AADC01.

All three patient groups were able to reduce their intake of levodopa equivalent doses within six months of treatment. The mean decrease was 15% for the lowest gene therapy dose, 33% for the middle one, and 42% for the highest one.

“Given the improvements in motor function and wider spectrum to titrate oral levodopa with our Cohort 2 dose, we are excited to consider this as our likely dose in the pivotal program while still planning to review the six-month results from the Phase 1 posterior trajectory trial next quarter,” Bernard Ravina, the chief medical officer of Voyager Therapeutics, said in a news release.

VY-AADC01 also generated durable improvements in other measurements of motor function, including reductions in daily on-time with troublesome dyskinesia, or involuntary muscle movements.

In patient group 1, the improvement in on-time without troublesome dyskinesia was 2.1 hours at three years after treatment. In group 2 it was 3.5 hours at 18 months. And in group 3 it was 1.5 hours at 12 months.

Quality of life also improved in a dose-dependent manner, measured by patients’ scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and on the 39-item Parkinson’s Disease Questionnaire (PDQ-39).

Infusions of VY-AADC01 were well-tolerated in all patients, with no serious adverse events, supporting previous safety findings.

“We continue to be pleased with the duration and magnitude of effect of VY-AADC on multiple measures of patients’ motor function and quality of life, which is consistent with the mechanism of action of VY-AADC suggesting a greater capacity for patients to make more dopamine and improve their motor function with less need for oral levodopa,” Ravina said.

Voyager expects to use data from the Phase 1 and Phase 1b trials to design a Phase 2-3 pivotal trial program, which is expected to start mid-2018.

“We look forward to reviewing these results from the Phase 1b with the FDA,” Ravina said. “And we continue to expect to dose the first patient in the pivotal Phase 2-3 program in mid-2018.”

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Levodopa May Not Be the Best Option for Parkinson’s Treatment, Study by Students Contends

Levodopa shortcomings

Levodopa improves Parkinson’s patients’ symptoms by binding with two types of receptors for dopamine, a neurotransmitter that helps regulate movement and emotional response.

Although it is considered the gold standard in Parkinson’s treatment, a study from Binghamton University students contends that levodopa’s interaction with the dopamine receptor D2 may cause involuntary muscle movements, compulsive behaviors, and hallucinations.

The research, “Effects of Receptor-Specific Dopamine Drugs on the Treatment of Cognitive Deficits in Parkinson’s Disease,” appeared in the The Undergraduate Journal of Psychology at UCLA.

Parkinson’s is a progressive neurodegenerative disorder that affects movement, muscle function, and speech. It is characterized by gradual loss of nerve cells that contain the neurotransmitter dopamine. They are located in a brain area called substantia nigra that is essential to the control of movement.

Dopamine binds to two classes of receptors — D1 and D2. Levodopa, which is also called L-DOPA, is a naturally occurring molecule that generates dopamine. It binds to both D1 and D2 receptors to replenish the disease-related lower levels of dopamine, improving Parkinson’s symptoms.

The New York State university research team triggered the formation of brain lesions in rats to mimic the loss of nerve cells in Parkinson’s. Rats were then treated with levodopa or compounds that bind with either D1 or D2 receptors, but not both. The next step was for rats to be tested for movement, ability to pay attention, and spatial memory.

Although activating D2 receptors with quinpirole improved the rats’ spatial memory, it led to  attention loss in both rats with brain lesions and controls. In contrast, activating D1 receptors did not lead to significant differences, in comparison with levodopa.

Overall, the findings suggested that, because levodopa stimulates D2 receptors, it may not be the best choice for Parkinson’s treatment.

“Parkinson’s disease is one of the most common neurodegenerative diseases in the world,” Lakshmi Hareendran, a member of the research team, said in a press release. “Knowing that the current treatment isn’t as effective as it could be is important.”

“In conclusion, the quinpirole effects on memory and attention ability is an essential discovery. Uncovering the mechanisms underlying these actions may lead to the development of a more effective treatment for [Parkinson’s] that covers both motor and cognitive deficits in humans,” the researchers wrote.

Hareendran comes from a family with several doctors and has an uncle who is a brain surgeon. “As a kid, just thinking about him being able to understand something as complex as the human brain really inspired me to go down that path,” she said. She plans to work with Doctors Without Borders some day.

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Adamas Is Getting the Word Out on Its Parkinson’s Muscle Control Therapy

Muscle control therapy

Adamas Pharmaceuticals is making a concerted effort to spread the word on its flagship treatment for the involuntary muscle movements that are a hallmark of Parkinson’s disease.

The U.S. Food and Drug Administration approved Gocovri (amantadine) in August 17. Adamas began making the extended release capsules available in the United States in October 2017.

It has now assembled a 59-person team to acquaint doctors and patients with it. It is calling the deployment of the team its U.S. launch of Gocovri.

Involuntary muscle movements, which disrupt daily activities, affect an estimated 90 percent of Parkinson’s patients.

Gocovri is the first and only treatment the FDA has approved for involuntary muscle movements, or dyskinesia, in Parkinson’s patients who are taking levodopa. The approval covers patients on levodopa by itself or a combination of levodopa and other dopamine-generating agents.

Dopamine is a chemical that is essential to transmitting brain signals to the muscles and controlling movement. Parkinson’s affects nerve cells responsible for producing dopamine. The loss of the neurotransmitter leads to a progressive deterioration in muscle coordination and movement.

One of the first lines of treatment for Parkinson’s is using levodopa to replace dopamine. But its long-term use can disrupt the balance of chemical messengers that control movement, causing dyskinesia.

“The launch of Gocovri, which was demonstrated in clinical studies to reduce both dyskinesia and OFF time, gives physicians a new tool for the treatment of Parkinson’s disease patients with dyskinesia,” Dr. Rajesh Pahwa, who directs the University of Kansas Medical Center’s Parkinson’s Disease Center, said in a press release.

Clinical trials have shown that Gocovri can increase the release of dopamine.

Gocovri offers doctors an alternative to managing dyskinesia that can avoid levodopa’s widespread side effects.

In a related development, Adamas has established a program to help patients obtain access to Gocovri. The Gocovri Onboard initiative includes prescription-filling and financial assistance. More information is available on the program’s website.

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