Accordion Pill May Help Reduce Motor Fluctuations in Parkinson’s Disease, Phase 2 Trial Shows

Accordian Pill, Parkinson's

The Accordion Pill Carbidopa/Levodopa (AP-CD/LD) administered three times a day reduced the variability of blood plasma levels of levodopa in Parkinson’s disease patients, which suggests that the treatment may help to ease motor fluctuations, a Phase 2 trial shows.

Warren Olanow, MD, professor at Mount Sinai School of Medicine, New York, and the study’s lead author shared these results in a scientific poster, titled “Pharmacokinetics of multiple doses of Accordion Pill Carbidopa/Levodopa in patients with Parkinson’s disease,” at the 2019 IAPRD World Congress, June 16–19 in Montreal, Canada.

Levodopa is the most widely used treatment for Parkinson’s motor symptoms, and is almost always given in combination with carbidopa — a molecule that ensures levodopa is safely delivered to the brain, where it is processed to generate dopamine. Low levels of dopamine in Parkinson’s patients lead to the characteristic motor impairments associated with the disease.

However, patients with advanced disease who are being treated with levodopa often develop motor fluctuations, which result from “off” periods (when symptoms return) between levodopa doses due to its short-term effects.

This limited effectiveness is associated with the restricted absorption of levodopa in the upper part of the gastrointestinal tract, meaning that it has a short period of absorption.

Intec Pharma’s AP-CD/LD was designed to address this problem. The pill has a specific gastric retention and release system containing carbidopa and levodopa which allows the therapy to be released in both immediate and controlled-release modes.

Controlled release enables a slow discharge of the therapy in the stomach over eight to 12 hours, potentially allowing for more steady absorption in the upper gastrointestinal tract, where levodopa is absorbed.

The Phase 2 study (NCT03576638) evaluated the pharmacokinetic (PK) profile (a compound’s processing inside the body) of AP-CD/LD compared to Sinemet (an approved combination of immediate-release carbidopa-levodopa, marketed by Merck) in 12 Parkinson’s patients.

Participants received either an AP-CD/LD capsule — containing 50 mg of carbidopa with 500 mg of levodopa — three times a day, or they were given an immediate-release Sinemet tablet — consisting of 37.5 mg of carbidopa and 150 mg of levodopa — five times a day.

Blood samples were collected pre-dose, and then at 30-minute intervals post-dose over 16 hours and again at 24 hours post-dose.

The study’s main objective was to assess the variability in the blood concentration of levopoda between four and 16 hours after dosing.

The results showed that patients treated with AP-CD/LD three times a day had less variability in the concentration of levopoda in their blood compared with those given Sinemet given five times a day. Treatment with AP-CD/LD was found to be safe as there were no reports of adverse events.

As decreasing the fluctuations in blood levopoda levels is linked with reduced motor complications, “these preliminary results suggest that treatment with AP-CD/LD may reduce motor complications compared with standard [immediate-release]-CD/LD treatment in advanced [Parkinson’s disease] patients,” the researchers wrote.

“These PK results are important as they confirm our expectations that AP-CD/LD 50/500 [three times per day] reduces levodopa variability in [Parkinson’s disease] patients, which we expect will translate to a reduction in motor fluctuations in these patients,” Jeffrey A. Meckler, vice chairman and CEO of Intec Pharma said in a press release.

Intec Pharma is also conducting a Phase 3 trial, named ACCORDANCE (NCT02605434), to compare the safety and efficacy of AP-CD/LD and Sinemet in hundreds of adults with advanced Parkinson’s.

“We are eagerly awaiting the top-line results from our Phase 3 ACCORDANCE trial in the July/August time frame and these positive PK data support our belief that AP-CD/LD treatment could provide Parkinson’s disease patients with a better baseline [levodopa] therapy to reduce motor complications,” Meckler added.

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Report Showcases Benefits of Creativity Induced by Levodopa


A new report describes two Indian men with Parkinson’s disease who experienced “creative awakenings” after they started being treated with levodopa.

Appropriately titled, “A tale of two patients: Levodopa and creative awakening in Parkinson’s disease – A qualitative report,” the study was published in the Asian Journal of Psychiatry.

Levodopa is one of the mainstays of Parkinson’s treatment, and there have been scattered reports of people treated with it developing increased artistic creativity. The new study details the cases of two men, both from India, where levodopa-induced creativity has not been previously reported.

The first man, Mr. A, is a 68-year-old shopkeeper. He developed symptoms of Parkinson’s in 2010, and began treatment with levodopa in 2017.

Six months after he started on levodopa, Mr. A noticed some coconut shells lying in his yard and was struck by the urge to make something out of them. “It just happened, I just had these ideas,” he is quoted in the study as saying.

Mr. A began making various things out of the coconuts — pen holders, paperweights, cups, and more. He kept doing it, and now makes five to 10 such items per day.

Although he claims he was “not an artistic kind of person before all this,” Mr. A now sells his crafts at various shops. Although it’s not a full-fledged business, he says it does help him with his finances.

The second man, Mr. R, is a 63-year-old farmer who was diagnosed with Parkinson’s in 2011. He began levodopa treatment in 2015, and shortly thereafter, upon seeing his grandchild coloring, decided to start painting.

“I draw or paint all the time. I just can’t stop,” he said. “I’ve been doing it for nearly three years now.”

Mr. R, who regularly paints two or three pictures a day, has turned this newfound passion into a career. “Now it is a major source of income for me,” he said. “What gives me greater happiness is that I use the money I generate to support other people who need financial assistance for their medical needs.”

Both Mr. A and Mr. R are, on the whole, quite satisfied with the unexpected turns their lives have taken.

“I feel it’s given me a purpose in life,” said Mr. R. “If Parkinson’s disease was the only way I could have done all this, I won’t complain, honestly.”

“‘I am really happy. I don’t know what else to say,” said Mr. A.

It’s not clear exactly why levodopa treatment leads to creative awakenings in some patients. Several mechanisms have been proposed, such as:

  • “Creativity is a result of hyperactivity and behavioral disinhibition;”
  • “Creativity is a result of stimulation by dopamine agonists;”
  • “Creativity might be the emergence of innate skills in some predisposed Parkinson’s patients on dopaminergic therapy.”

However, in this report, researchers wanted to emphasize how this creative expression could be beneficial to patients.

“All in all, it would seem reasonable to assume that [making art] helped [Mr. A and Mr. R] cope positively with [Parkinson’s] and its deficits,” the researchers said. “Such artistic expression is therapeutic; it’s a form of art therapy, and we call for this usefulness to be further explored in routine clinical practice.”

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Zonisamide with Levodopa May Reduce Risk of Dementia, Other Parkinson’s-related Symptoms, Japanese Study Suggests

Zonisamide, Parkinson's

Japanese researchers have reported that zonisamide — an antiparkinsonian medicine approved in Japan as a combination therapy with levodopa — may be associated with a lower risk of dementia, insomnia, and gastric ulcers in Parkinson’s disease, compared with other non-levodopa medicines.

Their research was published in the study “Comparison of zonisamide with non-levodopa, anti-Parkinson’s disease drugs in the incidence of Parkinson’s disease-relevant symptoms,” in the Journal of the Neurological Sciences.

Marketed under the name Zonegran in the U.S. for adjunctive therapy in the treatment of partial seizures in adults with epilepsy since 2000, zonisamide has been approved in Japan (where it’s called Trerief) as an antiparkinsonian agent to be used in combination with levodopa therapy.

Parkinson’s patients have low levels of the chemical messenger dopamine in their brains due to disease-specific death of dopaminergic (meaning “dopamine-producing”) neurons. Among other brain functions, sleep, memory, and movement are all affected by the lack of dopamine and, as such, patients often develop insomnia and dementia, along with the hallmark motor symptoms of Parkinson’s disease.

Levodopa (L-DOPA) is the first choice when it comes to effective Parkinson’s motor symptom control, and as the disease progresses, patients typically need to gradually increase their treatment dose for maximum benefit. After that, they might sometimes experience reappearance or worsening of symptoms due to diminishing effects of dopaminergic therapy. Because of this, most patients will require combination therapy at some point.

Although zonisamide’s mechanism of action is not yet fully understood, studies indicate the compound acts by preventing the breakdown of dopamine, increasing its levels in the brain, and relieving Parkinson’s symptoms. Evidence also suggests that the medicine may have neuroprotective effects.

Clinical trials have shown zonisamide significantly alleviates Parkinson’s motor and non-motor symptoms. “However, partly because zonisamide is off-label for PD [Parkinson’s disease] except for in Japan, situations in which it is more suitable than other drugs have not been sufficiently elucidated,” the researchers noted.

For the study, investigators from Ehime University Graduate School of Medicine in Japan sought to evaluate if zonisamide use in Parkinson’s patients, 40 years or older, was associated with the time of onset of Parkinson’s disease-relevant symptoms, mainly mental, autonomic nervous system, movement, and gastric symptoms.

The results were compared to seven other non-levodopa drug classes that are often used when primary therapy is not fully effective (also referred to as second-line therapy).

For this analysis, levodopa was not considered as a comparison drug to zonisamide, as the majority of study participants were taking levodopa together with zonisamide or another second-line medicine.

Patients had to be on levodopa or other antiparkinsonian medicine without having switched to or recently combined use with other drug classes.

Using a set of statistical approaches, the researchers investigated the time it took for a given symptom of interest to occur while participants were on zonisamide, compared with other non-levodopa medications indicated for Parkinson’s disease.

Of the 9,157 studied subjects, those who were on COMT inhibitors, anticholinergics, or amantadine were two to nearly five times more likely to develop dementia. In addition, zonisamide use was found to be associated with a lower risk of developing insomnia and gastric ulcers, compared with three other non-levodopa medicines.

An increased prevalence of gastric ulcers has long been associated with Parkinson’s disease, and they are generally accepted as a symptom experienced by patients.

“Zonisamide also showed significant lower risk in the incidence of orthostatic hypotension, constipation, and limb fracture,” the researchers wrote, adding that the treatment was, however, also associated with a higher risk “in the incidence of depression and aspiration pneumonia than at least one of the other drug classes.”

Compared with three other classes of medications, zonisamide appears to be associated with a lower risk of developing dementia, insomnia, and gastric ulcers in Parkinson’s disease. However, it was not always the same three-treatment set that was found to be somehow associated with the lowest risk for a given symptom.

Nonetheless, “[t]here may be a potential clinical impact of zonisamide on some of the [Parkinson’s disease]-relevant symptoms,” the authors concluded.

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‘Framing OFF Through Art’ Exhibit on View at World Parkinson Congress

Artworks focus on off periods

More than 1 in every 3 — some 40 percent — of Parkinson’s patients have “off periods,” the return of motor and non-motor symptoms as the effectiveness of a  treatment’s dose wears off. Artworks created in collaboration with patients, part of an Acorda Therapeutics program, are helping to express what these periods are like and focus attention on them.

Called Framing OFF Through Art, the six-piece exhibition was recently featured at the 5th World Parkinson Congress in Kyoto, Japan, attended by more than 3,000 people from at least 60 countries. The initiative is the centerpiece of Acorda’s Live Well. Do Tell program, launched last year.

Off periods are characterized by the re-emergence of Parkinson’s symptoms, such as sadness and anxiety, when the effects of levodopa/carbidopa wear off. Such episodes are typically more common as the disease progresses, and vary from person to person.

Because off periods can be difficult to discuss or even identify, the artwork is intended to visualize feelings associated with them. The hope is that the art will spur other patients to recognize their “off” symptoms, and discuss them with their care team. The artists who created the pieces have been touched in some way by Parkinson’s.

”Research has consistently shown that off periods are among the most common issues for people living with Parkinson’s disease,” Ron Cohen, MD, Acorda president and chief executive officer, said in a news release.

“We believe that people with Parkinson’s will be able to see aspects of their own experiences with Parkinson’s and off periods in these works of art.”

The artwork ranges from acrylic sculptures to oil paintings. Each artist was paired with two patients and their caregivers. The exhibition debuted in October at a New York event where the artists, patients and caregivers were guests. The need to better understand off periods, as well as how to discuss them, is highlighted in the Live Well. Do Tell statement of need.

As part of a rotating series, a piece called “Rooted Resilience” is featured on the Live Well. Do Tell website. Created by abstract impressionist and colorist Tim Kinney, who has several friends with Parkinson’s, the multi-color painting of a tree depicts the way Gustavo Pavon, diagnosed in 2006, described his off periods.

The painting’s transition from dark roots to the brightness of the leaves and sky is meant to illustrate emergence from an off time.

Marcela Del Bosque, Pavon’s wife and caregiver, is mentioned in a narrative accompanying the painting as describing the transition in this way:

“When Marcela saw the painting, she immediately picked up on this and noted that when Gustavo is in a dark place — in an off period — he’s quiet and doesn’t smile. Then, Gustavo’s bright smile that she loves reappears and he returns.”

The work’s branches and colors also symbolize Pavon’s growth — his “branching out” —  to embrace community support and speak more openly about his experience. For nearly a decade, Pavon had only told a few people about his condition and off symptoms that include shivering and stiffness.

Go here to learn more about off periods and for additional resources.

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Blink Rate May Help Predict Blood Levodopa Levels in Parkinson’s Patients, Study Suggests

blink rate levodopa

Measuring how often a person spontaneously blinks could help predict motor changes in people with Parkinson’s disease being treated with levodopa, a study suggests.

The study, “Using Spontaneous Eye-blink Rates to Predict the Motor Status of Patients with Parkinson’s Disease,” was published in the journal Internal Medicine.

Levodopa is used as standard therapy for Parkinson’s disease, which is characterized by loss of dopamine-producing brain cells. The therapeutic formulation can cross the blood-brain barrier and enter the brain, where it is converted into dopamine. This dopamine then activates dopamine receptors and improves the function of movement control centers in the brain.

Especially in advanced disease, during which the body is making less of its own dopamine, maintaining just the right levels of levodopa in the blood is critical. The level of levodopa needs to be high enough to sustain a therapeutic effect, but if it gets too high, the patient may experience undesirable dyskinesia (uncontrolled body movements).

However, getting the level just right can be a fickle process. Levodopa is processed quite rapidly in the body, remaining actively stable inside the body for less than two hours, and its precise absorption pattern is governed by a complex set of interacting factors.

Thus, the level of levodopa has to be measured at multiple times in a patient to ensure that it is kept within more efficient levels. But this monitoring process requires taking multiple blood samples, which can be impractical and invasive. Therefore, researchers are investigating other strategies to assess levodopa levels without requiring blood samples. Previous research has demonstrated a connection between levels of dopamine in the brain and the rate at which a person spontaneously blinks.

Supported by these findings, Japanese researchers hypothesized that blinking rate could be correlated with levels of levodopa in the blood, and as such, blinking rates might be able to act as a more feasibly measurable proxy to assess levodopa levels.

To test this, the team gave a device that measures blinking to three people with Parkinson’s disease. The Jins Meme device is shaped like ordinary eyeglasses and is wirelessly connected to a computer, which processes the wearer’s data to calculate a “Blink Index.”

The researchers also collected blood samples every 15 minutes for the hour before the patients took levodopa, and then every half hour to one hour thereafter.

The blinking rate of the three patients varied widely over time. The researchers noted that blinking rates at the beginning of the study were quite high, which they believed could be due to the patients adjusting to the device. Despite this, blink rates did correlate with levodopa levels in the blood.

All the patients tended to have higher blinking rates when their levodopa levels were high, and vice versa. “This finding suggests that [blink rate] can be used as a substitute for plasma levodopa levels,” the researchers wrote. Therefore, “the continuous monitoring of [blink rate] may be useful for predicting the motor status in patients” with Parkinson’s.

Larger studies are needed to further validate and test the diagnostic potential of blink rates, the researchers said. Still, this study does serve as a proof-of-concept for using blinking rate as a proxy for levodopa levels in the blood of people with Parkinson’s.

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Gocovri Leads to Steady ‘On’ States in Parkinson’s Patients, Phase 3 Pooled Data Suggest


Gocovri (amantadine) can effectively reduce the number and duration of “off” periods and dyskinesia (uncontrolled movement) episodes in Parkinson’s patients under long-term levodopa treatment, leading to a good steady “on” state, pooled Phase 3 clinical data show.

These findings were reported in a study, “Prevalence of Dyskinesia and OFF by 30-Minute Intervals Through the Day and Assessment of Daily Episodes of Dyskinesia and OFF: Novel Analyses of Diary Data from Gocovri Pivotal Trials,” that was published in the Journal of Parkinson’s Disease.

Levodopa is a precursor of dopamine and one of the gold-standard treatments to manage the motor symptoms of Parkinson’s disease. However, patients who take it over extended periods develop off-episodes, moments in which the therapy losses its effect and involuntary movements (dyskinesia) reappear.

Some adjustments and alternative treatments, such as Gocovri (marketed by Adamas Pharmaceuticals), can help control these off-episodes and dyskinesia. But it is not clear how these treatments act as a whole.

Therefore, the researchers reviewed the effects of Gocovri from data collected during two Phase 3 placebo-controlled trials, called EASE LID (NCT02136914) and EASE LID 3 (NCT02274766).

The analysis included data from 162 Parkinson’s patients who participated in these trials, of whom 77 received Gocovri and 85 received a placebo for 12 weeks. The patients had a mean age of 64.5 years, had been diagnosed with Parkinson’s disease for 9.9 years, and had been taking levodopa for about 7.6 years.

During the trials, patients kept diaries in which they were asked to detail their daily on- and off-periods, and events of dyskinesia. Patients divided their awake time into 30-minute intervals and reported the state they were in at each interval.

Three main states were considered: “on” without troublesome dyskinesia (good “on”), “on” with troublesome dyskinesia (troublesome dyskinesia), and off-periods. Troublesome dyskinesia referred to involuntary movements that impaired, at least partially, the performance of daily functions.

Most patients (67%) reported waking up in an off-state, which decreased to 13% of patients during the first two awake hours. Thereafter, the number of patients in each state remained constant throughout the day.

A lower number of patients (5%) woke up experiencing troublesome dyskinesia, which in contrast increased up to 24% within the two hours after being awake, then fluctuated between 20% and 44% through the rest of the waking day.

Patients were found to experience a mean of 3.0 episodes of troublesome dyskinesia and about 2.2 off-episodes during the day. The mean duration of each episode was approximately two hours for dyskinesia and 1.1 hours for an off-episode.

After taking Gocovri for 12 weeks, the proportion of patients reporting no episodes of “on” with troublesome dyskinesia was 57.1%, compared with 24.7% in the placebo group. The treatment also reduced the mean duration of the episodes and the mean number of transitions between states during the day, leading to a steadier good “on” state during the day.

In general, the treatment was found to be safe, with less than 10% of patients experiencing adverse events. The most common adverse events were dizziness, constipation, hallucinations, dry mouth, edema, swelling of the extremities, and urinary infections.

“Our results demonstrated a treatment effect of Gocovri for dyskinesia and OFF [states] throughout the waking day,” the researchers wrote.

“In the future, wearable sensors and other types of monitors may provide continuous monitoring through the day and allow more sensitive assessment of mild motor fluctuations and dyskinesia,” they said.

Of note, most of the researchers received compensation from or are employees of Adamas Pharmaceuticals.

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Levodopa-Sparing Medications May Help Patients in Early Stages of Parkinson’s, Study Suggests

Early stage Parkinson's, Levodopa-Sparing Medications

Neurologists treating patients with early-stage Parkinson’s disease should prescribe more often therapies that spare patients from starting levodopa too soon in order to delay onset of side effects associated with long-term use of the medicine, findings from a study conducted in Romania suggest.

Researchers believe that even if a doctor believes a patient’s clinical situation required management with levodopa, they should first try to combine it with other antiparkinsonian therapies — such as other dopamine agonists or monoamine oxidase B inhibitors — in order to allow lower levodopa doses.

These findings resulted from a study, “Therapeutic strategies in the early stages of Parkinson’s disease: a cross-sectional evaluation of 15 years’ experience with a large cohort of Romanian patients,” which was published in the journal Neuropsychiatric Disease and Treatment.

Currently, the most effective and cost-saving therapy for lessening Parkinson’s symptoms is substitution therapy with levodopa. However, a major drawback of this therapy is the side effects associated with its long-term use.

After four to six years of treatment with levodopa, many patients may start experiencing spontaneous involuntary movements (dyskinesia), with some patients also having impulsive and compulsive behaviors. Its effectiveness can also reduce over time, causing patients to experience wearing-off effects, meaning that the therapy loses its ability to effectively manage Parkinson’s symptoms before it is time for the next dose.

Some clinical evidence seems to indicate that in many cases “if the therapy is started too early and with high doses, these complications may appear earlier and can be more severe, especially in younger patients,” the researchers wrote. This leads clinicians to try to avoid these side effects and adverse reactions by limiting levodopa doses as much as possible.

Based on clinical efficacy data from newer antiparkinsonian therapies in younger patients (under 60 years), European guidelines propose the use of levodopa-sparing medications as a first option for early-stage patients to delay the onset of motor and non-motor complications. But there is little real-world data to confirm how these therapeutic recommendations are being applied in clinical practice.

Therefore, the researchers reviewed the medical records of patients with early-stage Parkinson’s hospitalized between 2003 and 2017 at Târgu Mures Emergency County Hospital, in Romania, to gather real-world data on the use of levodopa and alternative therapies.

During this 15-year period, a total of 2,379 patients with Parkinson’s were hospitalized, of whom 1,237 had received the diagnosis for five years or less. The researchers justified this time window because most practicing neurologists consider that the efficacy of levodopa-sparing treatment strategies is significantly reduced after a five-year period. Only patients with early-stage disease were included in the study.

In this group, 18 patients (1.5%) were receiving monoamine oxidase-B inhibitors (MAO-Bi). A total of 665 patients were taking dopamine agonists, of whom 120 were taking the therapy alone (9.7%) and  83 patients (6.7%) in combination with MAO-Bi. Many of the patients (42%) were only taking levodopa, while 481 patients (38.8%) were taking levodopa in combination with other antiparkinsonian therapies.

Assessment of levodopa daily doses, either alone or in combination with other therapies, did not reveal any significant differences between patients grouped by age (younger than 50, 50–65, or older than 65).

“The therapeutic strategies used in the early stages of Parkinson’s disease in the study period are similar to those found in the literature,” the researchers wrote. Still, they recommend that “neurologists treating this disease should, with due diligence, apply a greater proportion of different levodopa-sparing combinations, especially if they are not financially burdensome.”

What makes clinicians decide to prescribe levodopa or other dopamine agonists in the first place is difficult to access through this study, and can be influenced by a number of factors, the researchers said.

“Because our study looks at a long period it is hard to retrospectively assess how much of the clinical decisions was influenced by the early optimism (as reflected in the initial studies) regarding the potential disease-modifying effect as well as the magnitude of the clinical efficacy of dopamine agonists,” they added.

Still, “if the severity of the clinical image requires substitution therapy, the use of combined therapies can significantly reduce levodopa doses and thus the requirement to use the minimum efficient levodopa dose can be achieved,” they concluded.

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#AANAM – L-DOPA Nasal Delivery System May Offer New Way to Manage Parkinson’s OFF Episodes

POD device powder L-DOPA

Impel NeuroPharma has developed an inhaler to administrate a powder formulation of levodopa (L-DOPA) so people with Parkinson’s disease can more easily manage their symptoms.

Evidence of the potential of this new treatment strategy was presented at the 2019 American Academy of Neurology (AAN) annual meeting in Philadelphia, in a poster titled “Preclinical Development of a Novel Precision Olfactory Delivery (POD®) – L-dopa Drug- Device Combination Product for the Treatment of OFF Episodes in Parkinson’s Disease.”

Levodopa is the gold-standard strategy used to achieve motor symptom relief in Parkinson’s disease. It is associated with the greatest improvement in motor function in these patients when compared with other available therapies designed to work in similar ways, and overcome the low dopamine levels in the brain that cause Parkinson’s.

Dopaminergic medications, including levodopa, enable Parkinson’s motor symptom control. However, as disease progresses, patients typically need to gradually increase treatment dose for maximum benefit and even after that they may still experience reappearance or worsening of symptoms (OFF periods) due to diminishing effects of the therapy. Evidence indicates that patients need to achieve 400 ng/mL L-DOPA levels circulating in the blood for their motor symptoms to ease.

The complexity of neurological disorders, the difficult access to the brain, and the high risks and costs of drug development represent serious disadvantages for improving therapies. Nose-to-brain drug transport offers an attractive alternative strategy attempting to enhance drug penetration into the central nervous system.

The Precision Olfactory Delivery (POD) device is a nasal therapy delivery system that allows easy access to a large tissue surface well-suited for rapid and consistent absorption of therapeutic compounds. Researchers manufactured more than 50 powder L-DOPA formulations and 30 of those were evaluated in preclinical animal models.

Researchers showed that using the POD system, it was possible to achieve 400 ng/mL L-DOPA levels circulating in the blood (the amount found to be clinically necessary to effectively ease motor symptoms) in about 5 to 12 minutes in non-human primates. This represents three- to five-fold improvement in levodopa delivery in comparison to currently available formulations.

Regarding anatomy or response to therapies, no other animal species is as close to humans as primates, so they are often used to test the safety and viability of therapies. They also allow an easier and truer extrapolation of findings to the “human reality,” making scientists better equipped to identify therapies that may reverse OFF episodes in Parkinson’s patients.

These preliminary results demonstrate that “a powder formulation of L-DOPA delivered to the vascular-rich upper nasal cavity with the POD device” can provide a way for self- or caregiver- administrated therapy and “achieve consistent and rapidly effective treatment to abort OFF episodes,” researchers said. “This work has led to the selection and further evaluation of a novel formulation in a Phase 2a clinical study.”

The study (NCT03541356) is currently recruiting patients with Parkinson’s disease at four clinical sites in Australia. For more information, visit the registry page here.

Up to 36 Parkinson’s patients, age 40 and up, will be randomized to take levodopa or a placebo administrated by a POD device. Researchers will assess the ability of the new formulation to manage OFF periods of motor symptom control, as well as its safety and tolerability.

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Wearable Sensors Help Assess Medication State in Levodopa-treated Parkinson’s Patients

Wearable sensors

Wearable motion sensors can allow doctors to objectively assess medication states in Parkinson’s disease patients being treated with levodopa, a new study shows.

The study, “Assessment of response to medication in individuals with Parkinson’s disease,” was published in the journal Medical Engineering & Physics.

Levodopa is the most common medication used to treat motor impairment in patients with Parkinson’s disease.

Unfortunately, long-term treatment with levodopa causes troubling motor impairments that are attributed to frequent fluctuations in the “on” and “off” periods. This refers to a phenomenon in which patients on levodopa switch between mobility and immobility, the latter developing when the dose has worn “off” but it is not yet time for the next dose.

The current method to address this problem is by adjusting therapy (i.e. medication frequency and dosage). However, this requires the doctor to know when the patient in the on and off state. This information is frequently obtained from patients’ self-reports, which can be biased.

The development of a wearable, sensor-based assessment system that can detect information about patients’ duration in medication on and off states can help improve therapy adjustment for Parkinson’s patients. Not only would this strategy help reduce motor fluctuations, but it would also improve associated healthcare costs.

Researchers from Florida Atlantic University’s College of Engineering and Computer Science have combined an algorithm and a sensor-based assessment system that can detect patients’ responses to treatment and medication states.

To test the system, researchers recruited 19 Parkinson’s patients and mounted two wearable KinetiSense motion sensors on their most affected wrists and ankles.

The team then collected movement signals as the participants performed daily activities, including resting, walking, drinking, dressing, hair brushing, unpacking groceries, and cutting food, in their medication off and on states.

The algorithm was trained using approximately 15% of the data from four activities and then tested on the remaining data. Hence, data from the two sensors can provide objective measurements instead of a patient diary or self-report.

“In a real-life scenario, the developed algorithm will be trained during a patient’s first visit. Then it will be used to detect the response to medication (on/off medication states) on a continuous basis and report objective information about the duration in on and off states to the treating neurologist for remote medication adjustments,” researchers said.

The algorithm was able to detect the response to medication during subjects’ daily activities with an average of 90.5% accuracy, 94.2% sensitivity, and 85.4% specificity.

Furthermore, the algorithm performed equally well for all the activities, with an average accuracy of 91.3% for the activities in the training phase and 88.4% for the new activities.

“The developed sensor-based algorithm could provide objective and accurate assessment of medication states that can lead to successful adjustment of the therapy, resulting in considerably improved care delivery and quality of life of patients,” researchers said.

The authors stress that this approach is novel in that it is customized to each patient rather than a “one-size-fits-all” approach.

“Once the algorithm is trained, it can readily be used as a passive system to monitor medication fluctuations without relying on patient or physician engagement,” Behnaz Ghoraani, PhD, an assistant professor in FAU’s department of computer and electrical engineering and computer science, said in a press release.

“There is a great need for a technology-based system to provide reliable and objective information about the duration in different medication phases for patients with Parkinson’s disease that can be used by the treating physician to successfully adjust therapy,” said Stella Batalama, PhD, dean of FAU’s College of Engineering and Computer Science.

“The research that professor Ghoraani and her collaborators are doing in this field could considerably improve both the delivery of care and the quality of life for the millions of patients who are afflicted by this debilitating neurodegenerative disease.”

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Antioxidants Protect Against Levodopa Toxicity, Mouse Study Shows


Antioxidants like vitamin C may protect against the toxic effects of levodopa, researchers report.

Their study, “Reducing oxidative toxicity of L-dopa in combination with two different antioxidants: an essential oil isolated from Rosa Damascena Mill., and vitamin C”, was published in Toxicology Reports.

Levodopa (L-DOPA) treatment effectively reduces early motor symptoms in Parkinson’s disease, but conflicting evidence suggests the therapy may further damage dopamine-producing neurons due to the overproduction of reactive oxygen species, a molecular phenomenon known as oxidative stress.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, resulting in cellular damage as a consequence of high levels of oxidant molecules.

In theory, combining levodopa therapy with antioxidants may decrease treatment-related side effects and help relieve symptoms.

Investigators from Trakia University in Bulgaria investigated whether L-DOPA-induced oxidative stress could be reduced by combining two distinct antioxidants — an essential oil isolated from Damask rose, and vitamin C.

To do so, healthy mice were divided into four groups. All animals, except the ones in the control group, received two intraperitoneal injections (injected directly into the body cavity) of L-DOPA and, after that, benserazide, a compound that increases the amount of L-DOPA crossing into the brain and its subsequent conversion to dopamine.

Two of the four study groups were pre-treated with injections of either rose oil or vitamin C before they were treated with L-DOPA and benserazide.

Scientists then screened for the presence of oxidative stress by measuring blood concentrations of particular proteins and lipids (fatty acids) that are known oxidative stress markers.

In comparison to the control sample, L-DOPA-only treated animals had a significant increase in molecular markers of oxidative stress, meaning that levodopa treatment induced oxidative stress in healthy animals.

Importantly, those same markers were significantly decreased in both groups pre-treated with antioxidants, compared to control animals.

“It must be emphasized, that Rosa damascene [Damask rose] oil exhibited behavior very similar to the classic antioxidants – vitamin C, making it potential candidates for extensive experimental research to their possible use as protectors against oxidative toxicity triggered by drug therapy of neurodegenerative diseases,” researchers concluded.

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