Stalevo May Be More Effective Than Other Medications for Early Parkinson’s, Meta-analysis Shows

Stalevo for Parkinson's

Stalevo (levodopa, carbidopa, and entacapone combination therapy) may be more effective but seems to be associated with more side effects than other medications to treat early Parkinson’s disease, researchers report.

The study, “Levodopa/carbidopa/entacapone for the treatment of early Parkinson’s disease: a meta-analysis,” was published in Neurological Sciences.

Levodopa (L-DOPA) is the mainstay treatment for Parkinson’s. As the disease progresses, patients typically need to gradually increase their dosage. Even after that, symptoms sometimes reappear or worsen (“off” periods) due to the dopaminergic therapy’s gradual loss of efficiency. Administration of levodopa in combination with both carbidopa and entacapone (LCE, sold by Novartis as Stalevo) has been shown to lessen symptoms and the number of “off” periods.

Although a large number of studies have investigated the treatment of Parkinson’s motor and non-motor symptoms, “there are still many controversies about the diagnosis and treatment of early [Parkinson’s disease] patients,” the researchers wrote.

In the study, a team led by researchers at University of Electronic Science and Technology of China studied the available data regarding the efficacy and safety of Stalevo in people with early Parkinson’s disease. These patients were identified as having idiopathic (of unknown cause) Parkinson’s, Hoehn and Yahr scale stage 3 or less (indicative of mild symptoms in one or both sides of the body), no motor complications history, no treatment, or limited use (generally less than six months) of anti-Parkinson’s medications.

The researchers searched the records of four biomedical databases up through October 2018. They looked for randomized clinical trials, written in English, that used Stalevo to treat early Parkinson’s.

The team analyzed six randomized clinical trials, which involved 1,983 participants (mean age of 60 to 70 years), with a mean average disease duration of 5.3 years.

The Stalevo group consisted of 983 participants and the control group had 1,000 participants. One study used levodopa/dopa decarboxylase inhibitor/entacapone and the remaining five adopted a levodopa/carbidopa regimen in the control group.

In all studies, treatment duration ranged from six to 134 weeks (about 2.5 years).

The Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s Disease Questionnaire (PDQ-39) were used to assess symptom severity and quality of life in four of the analyzed studies. The Clinician Global Impression of Change, which measures the change in a doctor’s global impression relative to the beginning of the study, was used as an outcome measure in two trials.

Stalevo was found to improve patients’ motor and non-motor experiences of daily living as measured by the UPDRS part 1 and 2, respectively.

Nonetheless, investigators did not notice any obvious differences between before and after treatment with Stalevo in the Clinician Global Impression of Change, which, according to the authors, could be explained “by a small amount of included studies.”

Also, when PDQ-39 was used as the outcome measure, Stalevo was found not to be as effective as levodopa-carbidopa alone. One possible reason for this is that using PDQ-39 scores may not be sensitive enough to detect changes in these measures in early Parkinson’s patients.

“LCE therapy also increased the risk of total AEs [adverse events], nausea, diarrhea, dyskinesia, dizziness, urine abnormality, and discontinuation risk when compared with traditional therapy,” the researchers wrote.

Around 80.4% of patients treated with Stalevo experienced side effects, compared with 66.8% of those in the control group. Importantly, patients on Stalevo had nearly three times the risk of developing urine abnormality at some point than controls.

Compared to other Parkinson’s medications, and despite the higher percentage of side effects, Stalevo appears to be more effective in the treatment of early Parkinson’s. Still, the researchers advise that these results should be interpreted carefully as this meta-analysis included only six studies.

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MJFF Supports Lundbeck Research in Diagnosing Parkinson’s

Lundbeck grant

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) is supporting efforts by pharmaceutical company Lundbeck to find a new way to diagnose Parkinson’s Disease patients earlier and more effectively.

With a $1.3 million DKK (Danish krone) grant ($197,000 U.S.), Lundbeck plans to develop and validate a diagnostic test that uses the cerebrospinal fluid that flows in and around the brain and spinal cord. Such a tool could speed initial treatments to patients. Currently, there are no specific tests to confirm Parkinson’s.

Study results will be shared with the pharmaceutical industry, academia and the Parkinson’s community in general.

“We are pleased to receive this grant from The Michael J. Fox Foundation,” Johan Luthman, executive vice president for research and development, Lundbeck, said in a press release. “We still see a great unmet medical need in Parkinson’s disease today, and hopefully this research can help diagnose the disease earlier and thereby improve the outcomes for patients,” he said.

The test that Denmark-based Lundbeck hopes to develop is known as a biomarker assay, a tool that can measure various substances in the body. Specifically, the assay seeks to gauge levels of Parkinson’s-associated alpha-synuclein. Parkinson’s is characterized by aggregates of this protein in the nervous system, particularly in the brain’s dopamine-producing neurons. However, how these aggregates form isn’t fully understood.

Nearly 20% of individuals diagnosed with Parkinson’s have a different disease with symptoms similar to those commonly experienced by Parkinson’s patients, Lundbeck said. The main motor Parkinson’s symptoms include tremor, slowness of movement (bradykinesia), muscle stiffness, postural instability, gait difficulties and vocal changes. Non-motor symptoms range from depression and anxiety to hallucinations, memory problems and dementia.

For diagnoses, clinicians usually rely on symptoms, imaging tests and a levodopa test, in which a neurologist recommends a sufficient dose of the Parkinson’s therapy to see if it helps symptoms.

“A biological marker of Parkinson’s disease would transform patient care and research, allowing earlier and more accurate diagnosis and more efficient therapeutic testing,” said Luis Oliveira, PhD, MJFF associate director of research programs. “Aggregated alpha-synuclein is a leading biomarker candidate, and our Foundation is pleased to support Lundbeck toward measurements of this pathological protein.”

The nonprofit organization previously has supported Lundbeck projects focused on Parkinson’s antibodies, understanding the LRRK2 gene — whose mutated form is one of the most common genetic causes of Parkinson’s — and two new disease targets.

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Scientists Uncover New Therapeutic Molecule BT13 That May Possibly Protect Against Neurodegeneration

therapeutic molecule BT13

Scientists have uncovered a new therapeutic molecule, called BT13, that can get to the brain to boost dopamine levels — the brain chemical that’s in short supply in Parkinson’s disease — and could potentially protect against neurodegeneration.

While the research is in the early stages, and the molecule has only been tested in mice and cellular models of the disease, the researchers say BT13 shows promise as a way to slow or stop Parkinson’s instead of just treating its symptoms.

The findings were described in the study, “Glial cell line–derived neurotrophic factor receptor Rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo,” published in Movement Disorders.

Evidence shows that a small protein known as glial cell line-derived neurotrophic factor, or GDNF, supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease.

In animal models of Parkinson’s, as well as in human clinical trials, GDNF has shown neuroprotective effects.

However, due to its large size, GDNF is not able to cross the human blood-brain barrier (BBB), and complex surgery is required to deliver the treatment to the brain. The BBB is a semipermeable membrane that protects the brain against the external environment, but is a major barrier for the efficient delivery of therapies that need to reach the brain and central nervous system to work.

BT13, another molecule that binds the same signaling receptor — or RET receptor — for the GDNF molecule family, is much smaller in size than GDNF. Researchers say BT13 has the potential to produce the same neuroprotective effects as GDNF and should be able to more easily cross the blood-brain barrier.

Now, a team of scientists from the University of Helsinki in Finland set out to study this small molecule’s effects in immortalized nerve cells — neurons that are engineered to proliferate indefinitely — and in live mice.

The results revealed that after binding to RET, BT13 triggered molecular signaling cascades related to cellular survival and growth in normal dopamine-producing immortalized neurons. However, when cells were engineered to lack the RET receptor, BT13 had no effect.

BT13 was found to protect against Parkinson’s-related neurodegeneration, which was simulated in the lab by exposing dopaminergic neurons in dishes to 6-OHDA and MPP+ — both neurotoxins that induce cell death and mimic disease symptoms. Importantly, BT13 only protected these neurons when they expressed the RET receptor.

In addition, when BT13 was administered to mice — through an injection directly into the brain — it was able to cross the blood-brain barrier. When in the brain, the molecule activated cell survival and growth pathways and promoted the release of dopamine from the animals’ striatum, a motor control brain area primarily affected by Parkinson’s.

“People with Parkinson’s desperately need a new treatment that can stop the condition in its tracks, instead of just masking the symptoms. One of the biggest challenges for Parkinson’s research is how to get drugs past the blood-brain barrier, so the exciting discovery of BT13 has opened up a new avenue for research to explore, and the molecule holds great promise as a way to slow or stop Parkinson’s,” David Dexter, PhD, deputy director of research at Parkinson’s UK and professor of neuropharmacology at Imperial College London, said in a press release.

“We are constantly working on improving the effectiveness of BT13,” said Yulia Sidorova, PhD, the study’s lead researcher. “We are now testing a series of similar BT13 compounds, which were predicted by a computer program to have even better characteristics.

“Our ultimate goal is to progress these compounds to clinical trials in a few coming years,” Sidorova said.

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European Project Seeks to Develop Implantable Nanodevices for the Brain to Treat Parkinson’s and Epilepsy

early trial results

A three-year project in Europe seeks to develop nanodevices that could be used as brain implants to treat neurological disorders such as Parkinson’s disease and epilepsy.

The European Commission is funding the 3-million euro ($3.3-million) project, called Ion Neuromodulation for Epilepsy Treatment (IN-FET), which aims to create new implantable devices to fundamentally modulate the brain’s electrical activity.

Launched last month, the project, led by Scuola Internazionale Superiore di Studi Avanzati (SISSA), zeroes in on ions such as magnesium, potassium and calcium — nerve cell communication messengers.

“Today’s cutting-edge experimental therapies for restoring or repairing brain functions in neural disorders often involve modulating or silencing hyperactive brain circuits,” said Michele Giugliano, director of SISSA’s Neuronal Dynamics Lab, in a press release.

“This can be done by pharmacological or genetic manipulations, or by delivering electrical, magnetic or optical stimuli to the brain. All of them, however, come with serious drawbacks, due to the unnatural means to regulate the activity of nerve cells. Our idea is to use what the brain normally uses to function: ions.”

The plan is to develop implantable devices to alter the concentration of the most common ions on a cellular scale. The hope is that such devices will be able to measure neuronal electrical activity and, if necessary, correct it.

Led by Trieste, Italy-based SISSA, the project is undergirded by advancements in new-generation electronic batteries that use highly efficient electro-activated polymers. In this application — for patients with Parkinson’s or epilepsy — polymers would be used like “molecular machines” to trap or release certain ions into areas enveloping neurons.

“This way we could work on neurons activity by means of their own language, the one they normally use to communicate,” Giugliano said. “With this method, we could treat neurological diseases through a very natural means, which could be much more effective. Compared to the approaches currently used to study and treat neurological diseases, it is a change of perspective.”

By testing the devices on nerve cells in vitro (in a test tube or culture dish), the IN-FET project will attempt to learn whether the perspective is correct.

University of Sheffield and IBM Research scientists will develop the molecular devices, while the University of Geneva and the Inter-University Consortium For Nanoelectronics will build supportive theoretical models. Multi Channel Systems will handle integration and electronic interfacing.

“We are trying to open a truly new road towards a world waiting to be discovered,” Giugliano said. “We will work hard to achieve this, ready to be amazed.”

Nearly one million people are thought to have Parkinson’s in the United States.

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Personalized Brain Maps May Help Improve Deep Brain Stimulation for Parkinson’s, Other Conditions

deep brain stimulation

Not everyone’s brain connections map at exactly the same location, which may explain why deep brain stimulation (DBS) therapy, used for severe cases of Parkinson’s and other neurological conditions, works for some patients and not for others, a study has found.

The findings,”Integrative and Network-Specific Connectivity of the Basal Ganglia and Thalamus Defined in Individuals,” could improve DBS treatment for Parkinson’s patients, by helping doctors choose where in the brain to implant electrodes based on each patient’s own brain maps. The research was published in the journal Neuron.

DBS — a surgical procedure in which electric stimulators are placed at target regions inside the brain — may be used to relieve motor symptoms in some people with Parkinson’s, who have had the disease for at least four years and whose motor symptoms cannot be fully controlled by medication.

It usually works best to ease stiffness, slowness, and tremor, and not as well for imbalance, sudden inability to move when walking, or non-motor symptoms.

For other neurological conditions, DBS can be used to ease cognitive symptoms such as obsessive thoughts and compulsive behaviors.

However, this method is not effective for all patients. In the case of Parkinson’s, it can be transformative for some, but for others, it causes side effects that outweigh the benefits, including worsened thinking or memory problems.

“Deep-brain stimulation is a very invasive treatment that is only done for difficult, severe cases,” one of the study’s leaders, Deanna Greene, PhD, a professor at Washington University School of Medicine in St. Louis, Illinois, (WUSTL) said in a press release.

“So it is difficult to grapple with the fact that such an invasive treatment may only help half the people half the time,” Green said.

She and her colleagues mapped specific circuits in the brain using magnetic resonance imaging (MRI) and found that each person’s brain networks position a bit differently. This may help explain why the effects of DBS vary so much from person to person and point to a potential way of improving the treatment.

It all started when a group of scientists from Washington University scanned themselves at night as part of the so-called Midnight Scan Club.

From the brain scans of 10 healthy individuals, researchers created three-dimensional maps of the functional networks running through structures located deep inside the brain, which usually are targeted by DBS and known as the thalamus and the basal ganglia.

Both these regions have been linked to neurological and psychiatric conditions, but so far the precise mapping of its activity has been  challenging technically.

Researchers discovered that the distinct networks that control vision, movement, attention, goal-directed behaviors, or the brain’s default state at rest, mingle and share information at nine hubs inside the basal ganglia and thalamus.

Importantly, they saw that each person’s functional networks can be positioned a bit differently, so when DBS electrodes are placed in the same anatomical spot they may influence different functions in different people.

Some networks and their connecting spots — such as the motor integration zone, where the control of movement and goal-directed behavior share paths — maintained pretty much the same location in all people. Of note, these regions corresponded to “consistently successful sites of deep brain stimulation,” the researchers wrote.

“I showed a neurosurgeon where we’d found the motor integration zone, and he said, ‘Oh, that’s where we put the electrodes for essential tremor, and it always works,’” said the study’s senior author, Nico Dosenbach, MD, PhD, and a professor at WUSTL.

Conversely, other networks and intersection points — some targeted to treat Parkinson’s disease — varied significantly more from person to person.

“We saw that there was a great deal of variation across people in terms of what functional networks are represented there, and deep-brain stimulation is only about 40% to 50% successful there,” Dosenbach said.

The team is now exploring ways of using each person’s brain map to personalize the best regions to target to provide relief while avoiding side effects. They also want to look for other brain spots that might provide even better results.

“What this study suggests is that a particular patient may do better if the wire is placed in relation to their personal functional brain map rather than in context of the population average. A personalized functional map — as opposed to an anatomical map, which is what we use today — could help us place a wire in the exact place that would provide the patient with the most benefit,” said study co-author Scott Norris, MD, professor at WUSTL.

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Parkinson’s Foundation to Present Spanish-language Conference Oct. 19

Parkinson's Foundation conference

The Parkinson’s Foundation’s fourth annual Spanish-language conference, set for Oct. 19 in Norwalk, California, will provide the latest information about Parkinson’s disease treatment and management.

Called “Hacia Adelante: Navegando el Mar del Parkinson’s” (“Forward: Sailing the Parkinson’s Sea”), the free conference is for patients, families, and healthcare providers interested in learning how to live well with Parkinson’s. All sessions and activities will be conducted in Spanish.

“Parkinson’s is more prevalent in Hispanics than in any other U.S. ethnic group, but studies confirm that many Hispanics are underserved when it comes to accessing necessary Parkinson’s information, treatment and care,” Fernando Cubillos, MD, the foundation’s senior director of research programs, said in a press release.

“As part of our mission to tackle this problem head on, we’re providing this conference to better empower and serve Latinos living with the disease through expert care, education and advocacy that is patient and community centered.”

In addition to presentations by a host of expert physicians and advocates, the event will include question-and-answer sessions, community resources, exercise and dance demonstrations, live music performances, and complimentary meals and parking. Grammy and Latin Grammy award-winning music producer Sebastian Krys will talk about his experience with Parkinson’s. The conference will take place from 9 a.m. to 3 p.m. at the DoubleTree by Hilton, 13111 Sycamore Drive.

Conference topics were chosen by the community. They include symptom management, healthcare system navigation, exercise, remaining motivated in the face of Parkinson’s, and caregiving as a family. Register here or by calling the bilingual Parkinson’s Foundation helpline at 800-473-4636.

On a related topic, the foundation presents a new episode of the podcast, “Substantial Matters: Life and Science of Parkinson’s,” every other Tuesday. In one episode — “What We’ve Learned from the Hispanic Parkinson’s Community” — Claudia Martinez, the Hispanic outreach coordinator at the Muhammad Ali Parkinson Center in Phoenix, describes the methods she uses to help Hispanic patients get the best possible care.

The most common neurodegenerative disease after Alzheimer’s, Parkinson’s affects nearly 1 million U.S. residents and 10 million globally. In the United States alone, 60,000 new cases are diagnosed annually.

The Parkinson’s Foundation works to enhance patient care and advance research toward a cure.

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Updated Canadian Guideline Reflects Latest Advances and Adds Palliative Care Section

Canadian Guideline Parkinson's

Updated recommendations on Parkinson’s disease have been published in the Canadian Guideline for Parkinson Disease, which includes a new section about palliative care.

Focused on issues relevant to the Canadian healthcare system, the update reflects the latest evidence and advances — particularly regarding diagnostic criteria and treatment options — and draws on recommendations from the United States, Scotland, the United Kingdom, and the European Union.

The Parkinson Canada-funded publication, which was published in the Canadian Medical Association Journal, offers fundamental guidance to healthcare professionals, patients, and families, and was developed with help from experts in Canada from various disciplines.

“This guideline provides evidence-based recommendations to improve the overall standard of care of individuals with Parkinson disease in Canada, not only for healthcare professionals, but also for policy makers, patients themselves, and their caregivers,” Veronica Bruno, MD, a neurologist with a subspecialty in movement disorders at the University of Calgary, said in a news release. “Managing the complexity of Parkinson disease requires clear, standardized procedures that can be used by all actors involved.”

The new guideline has five sections: communication, diagnosis and progression, treatment, non-motor features, and palliative care, which was added in this update. Palliative care, including an option of medically assisted death, should be considered throughout the course of the disease, the publication states.

“End-of-life choices, including advanced care planning with an open and frank discussion with the patient and the person designated as decision-maker, should be initiated early in the disease process,” the guideline says. “Conversations occurring in the ambulatory setting are likely to be more productive and less crises-driven than leaving such conversations until an acute stay in hospital.”

Other highlights include:

“A limitation to implementing the guideline is the lack of access to health care providers experienced in caring for people with Parkinson disease,” David Grimes, a neurologist at The Ottawa Hospital, said.

“In addition to specialist physicians, we need more nurses, and speech, occupational and physical therapists with training in this area, as well as adequate palliative care for Parkinson patients,” he added.

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Study Highlights Disparities in Patient and Physician Perceptions Of Parkinson’s

Parkinson's perspectives

A new study highlights some of the differences in perspective on disease management between people living with Parkinson’s disease and doctors treating them.

The study looks at non-motor symptoms, method of medication delivery, and awareness of support services as places where doctors’ and patients’ perceptions don’t line up, and suggests that getting these perceptions in better alignment could help improve treatment outcomes.

Patient and physician perceptions of disease management in Parkinson’s disease: results from a US-based multicenter survey” was published in the journal Neuropsychiatric Disease and Treatment.

The process of treating Parkinson’s disease is complicated and works best when both patients and doctors are on the same page. When there is disconnect, treatment is more likely to be less than optimal, particularly in terms of patients’ quality of life.

To identify such areas of divergence in perspective, researchers developed a questionnaire, which they gave to physicians treating Parkinson’s patients. The physicians’ patients were given a separate questionnaire to complete.

In addition to gathering demographic and health data, the questionnaires included more subjective questions about treatment regimes. For example, both physicians and patients were asked about the effect of Parkinson’s on patients’ quality of life, and both groups were asked about patient satisfaction with medications. There were also questions about what a conversation between a physician and a patient might look like.

The questionnaire was sent to 107 physicians, 70 of whom responded and provided answers regarding 350 different patients. Additionally, 71 patient questionnaires were completed and collected. Of all these, there were 66 patients for whom both physician and patient questionnaires were completed, allowing for the most direct comparison.

There were many areas in which physicians and patients were in agreement. For example, both groups rated the efficacy and safety of a potential treatment as very important in selecting treatments, as would be expected.

Generally, patients and physicians also had similar perceptions on how Parkinson’s was affecting patients’ quality of life, even though physicians reported that this isn’t often formally assessed. The researchers noted that doing such assessments more often might further improve Parkinson’s treatment.

There were also some areas where patients and physicians reported significantly different views.

Patients rated the form of medication delivery (e.g. a pill versus an injection) as more important than physicians in deciding what the best treatment is.

Physicians reported spending more time during patient visits discussing motor symptoms (e.g. tremors, which they felt were most bothersome for most patients) than non-motor symptoms (e.g. depression and anxiety).

In contrast, patients reported a perception of a fairly even split.

“From a physician perspective, there was alignment between the motor symptoms that were most bothersome for patients and those that were most discussed … but disconnect between the most bothersome and most discussed non-motor symptoms (physicians felt fatigue was most bothersome for most patients … [and] cognitive impairment was the most discussed non-motor symptom…),” researchers said.

Finally, physicians tended to view their patients as more knowledgeable about Parkinson’s disease than did the patients themselves. This extended to physicians being much more aware of available support services than the patients.

Nonetheless, this study has numerous limitations, including its sample which, in addition to being small, probably isn’t representative of Parkinson’s patients in terms of age, education, disease status, etc. The study also focused only on patients in the United States, potentially limiting its ability to be generalized.

However, the investigators propose that getting patients and physicians on the same page about these issues could be clinically helpful.

“Non-motor symptoms, form of medication delivery, and awareness of support services are areas where physician and patient alignment could be increased to potentially improve patient outcomes,” they concluded.

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Levodopa Shows No Disease-modifying Effects in Parkinson’s, Study Finds

levodopa study

Levodopa/carbidopa treatment is effective in managing Parkinson’s motor symptoms, but does not protect against disease progression among patients with early disease, a study shows.

The research, “Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease” was published in The New England Journal of Medicine.

Levodopa is the main treatment for Parkinson’s disease. However, neurologists might delay prescribing levodopa for different reasons, including concern about the development of levodopa-induced dyskinesias (abnormal, uncontrolled, involuntary movements), which is one of the most common dose-limiting side effects of this treatment approach.

However, almost all patients eventually receive levodopa to control their motor symptoms.

In an earlier clinical trial, called ELLDOPA , 361 patients with early Parkinson’s disease received levodopa or placebo for 40 weeks. Two weeks after that, clinical examination showed that the participants who had received levodopa had a slower disease progression than those on placebo. However, brain imaging studies revealed that levodopa had either accelerated the death of dopaminergic neurons, or it had modified the protein responsible for the transport of dopamine in brain nerve cells.

“Therefore, whether levodopa has an effect on the progression of Parkinson’s disease beyond its immediate benefit with respect to symptoms remains unknown,” scientists wrote.

Now, researchers from the University of Amsterdam designed a multicenter, randomized, placebo-controlled, delayed-start trial to assess levodopa’s effect on patients with early Parkinson’s disease who had insufficient disability to receive anti-Parkinson medication: the Levodopa in Early Parkinson’s Disease (LEAP) study (ISRCTN30518857).

Patients who had received their diagnosis within the previous two years were randomly assigned to an early-start group (207 subjects): levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks; or to a delayed-start group (210 participants): placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks.

During Phase 1 (the first 40 weeks of the trial), patients received levodopa or placebo. During Phase 2 (the second 40 weeks) patients in both trial groups received levodopa. Assessments were made at baseline (trial initiation) and at weeks 4, 22, 40, 44, 56, 68, and 80.

The study’s primary endpoint (goal) was the difference in the mean change, from trial initiation to week 80, in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS). That tool assesses both motor and non-motor symptoms associated with Parkinson’s disease (higher scores indicate more severe disease).

Secondary outcomes included the progression of symptoms between weeks 4 and 40 and between weeks 44 and 80, as measured by the category scores on the UPDRS; disability; cognitive impairment; depression; and disease-related quality of life.

At week 80, there was no significant difference between the early-start and delayed-start group regarding motor and non-motor symptoms, as measured by the UPDRS, indicating that levodopa had no disease-modifying effect.

To test if early treatment initiation was prognostically better than a delayed one or vice-versa, scientists compared symptoms’ progression rate in week 4-40 and week 44-80. Once again, no significant changes were observed between groups in either study period.

No significant changes in therapy-related motor fluctuations, including dyskinesias, were found between groups. During the first 40 weeks, patients on the early-start group complained more of nausea (23%), compared to the participants on the delayed-start group (14.3%).

Also, no significant differences were observed regarding disability, cognitive impairment, depression and disease-related quality of life between the groups.

“We conclude that treatment with levodopa at a dose of 100 mg three times per day in combination with carbidopa at a dose of 25 mg three times per day had no disease-modifying effect, either beneficial or detrimental, on early Parkinson’s disease among patients who were evaluated over the course of 80 weeks. Whether higher doses of the drug, longer periods of administration, or initiation of the drug at later stages of the disease could alter the course of Parkinson’s disease warrants evaluation in future trials,” researchers concluded.

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Gut Bacteria Affect Metabolism of Parkinson’s Therapy Levodopa, Study Shows

gut bacteria

Levodopa, one of the main medicines used to treat Parkinson’s symptoms, can be converted into dopamine by gut bacteria, researchers report.

The findings might explain why levodopa treatment is less effective in some patients.

The study, “Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease,” was published in Nature Communications.

Parkinson’s disease is characterized by low levels of dopamine, a chemical brain messenger essential for neurons involved in movement control.

In terms of treatment, patients cannot take dopamine directly, as the compound is broken down by the body before it reaches the brain. Levodopa crosses the blood-brain barrier and is taken up by dopaminergic neurons, which convert the chemical into dopamine, which helps manage disease-related motor symptoms.

Studies have suggested that gut bacteria can affect treatment effectiveness in several diseases; particularly in Parkinson’s, the amount of levodopa that reaches the brain varies among patients.

“It is well established that gut bacteria can affect the brain,” assistant professor in microbiology Sahar El Aidy, PhD, and this study’s lead investigator, said in a press release. “There is a continuous chemical dialogue between gut bacteria and the brain, the so-called gut-brain axis.”

However, it remains to be explained if inter-patient variations in gut bacteria composition and functionality contribute to treatment response fluctuations in Parkinson’s disease patients who require a higher daily treatment dosage regimen.

Researchers from the University of Groningen in The Netherlands analyzed the effect of levodopa metabolizing bacteria in the middle section of the small intestine (jejunum), where levodopa is absorbed.

Using rat jejunum bacteria samples, researchers saw that an enzyme called tyrosine decarboxylase, which normally converts tyrosine into tyramine, also efficiently converted levodopa to dopamine in the gut. Enterococcus bacteria, commonly found in the intestines, were responsible for such enzymatic activity.

To understand if they could somehow inhibit levodopa’s conversion, the Dutch team “fed” the bacteria with a high concentration of the amino acid tyrosine, the main substance that tyrosine decarboxylase acts on, but tyrosine’s abundance did not prevent levodopa’s metabolization.

As part of their treatment regimen, Parkinson’s patients are given a decarboxylase inhibitor, like carbidopa, to block peripheral metabolism of levodopa to dopamine, allowing a greater concentration of levodopa to reach the brain.

Scientists studied the effect of human decarboxylase inhibitors, including carbidopa, benserazide, and methyldopa, on the bacterial tyrosine decarboxylase. None of the tested inhibitor compounds blocked levodopa’s enzymatic transformation.

“It turned out that, for example, the inhibitor carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase,” said El Aidy. This could be due to species-specific changes in carbidopa’s chemical structure, indicating that a more effective levodopa treatment could be achieved by co-administration of tyrosine decarboxylase inhibitor targeting both human and bacterial forms of the enzyme.

“[C]ommonly applied inhibitors of human DOPA [levodopa] [tyrosine] decarboxylase in levodopa combination therapy do not inhibit bacterial TDC [tyrosine decarboxylase] dependent levodopa conversion, implying levodopa/carbidopa (levodopa) combination therapy for PD [Parkinson’s disease] patients would not affect the efficacy of levodopa in situ [locally] by small intestinal bacteria,” researchers wrote.

These findings confirm the gut bacteria’s ability to influence local levels of levodopa treatment and suggest that the presence of tyrosine decarboxylase could reduce the amount of levodopa available in the bloodstream of Parkinson’s patients.

To test the latter hypothesis, investigators analyzed stool samples from patients who were on a normal or high dose of levodopa. They reported a strong positive correlation between the relative abundance of the bacterial gene encoding for tyrosine decarboxylase and the need for a higher levodopa/carbidopa treatment dose, as well as with disease duration.

To further understand the concept that the amount of tyrosine decarboxylase in jejunum’s bacteria affects bloodstream levels of levodopa/carbidopa and dopamine, scientists orally administered levodopa plus carbidopa to 18 wild-type (healthy) rats and analyzed animals’ blood 15 minutes after administration (time point when levodopa is at its higher concentration in rats).

Results showed that higher abundance of bacterial tyrosine decarboxylase in the rats’ jejunum decreased plasma levels of levodopa. The ratio between dopamine and levodopa/carbidopa levels in the small intestine positively correlated with bacterial enzyme amount.

Researchers then treated 10 rats with a subtype of Enterococcus bacteria known as Enterococcus faecalis that did not have the tyrosine decarboxylase gene and compared their levodopa/carbidopa plasma levels with 10 other rats that were given wild-type (normal, positive for the tyrosine decarboxylase gene) Enterococcus faecalis cells.

As expected, animals treated with wild-type cells had significant lower plasma levels of levodopa/carbidopa than the ones treated with mutant cells.

“Collectively, our data show that levodopa conversion by bacterial [tyrosine decarboxylase] in the small intestine should be considered as a significant explanatory factor for the increased levodopa/carbidopa dosage regimen required in a subset of [Parkinson’s disease] patients,” researchers wrote.

“This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment,” El Aidy said, referring to the involuntary, jerky movements patients experience.

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