Neupro Transdermal Parkinson's Patch Approved

A transdermal patch for early symptoms of Parkinson's disease has won FDA approval. 


The agent called Neupro represents both the first transdermal patch for Parkinson's and the first U.S. approval of any kind for the active ingredient, the dopamine agonist rotigotine, the agency announced.

The silicone-based patch delivers a measured dose of rotigotine, a nonergoline agent, over 24 hours.

According to the FDA, the effectiveness of Neupro was demonstrated in a fixed-dose response study and two flexible-dose studies. The parallel group randomized, double-blinded, placebo-controlled studies involved 1,154 patients with early Parkinson's who were not on other anti-Parkinson's agents.

The most commonly reported adverse events in clinical trials included patch-site skin reactions, dizziness, nausea, vomiting, drowsiness and insomnia. Other adverse events included narcolepsy-like sleep attacks, hallucinations, and postural hypotension.

In an open-label extension study of the patch, reported at the American Neurological Association meeting last October, the 137 patients on the active medication showed an immediate reduction in scores on the Unified Parkinson's Disease Rating Scale (UPDRS) of about seven points, and after six months that score remained four points below baseline.

At the end of the trial, the patients who had been on placebo and were then switched to the patch in the open-label extension phase showed an immediate drop in the Unified Parkinson's Disease Rating Scale scores, but as with the patients who continued on rotigotine, the scores slowly rose during the 85 week total length of the study, said Ray L. Watts, M.D., chairman of neurology at the University of Alabama at Birmingham.

In an early online release from the Jan. 23 issue of Neurology, Dr. Watts and colleagues reported that early-stage Parkinson's responded with significant relief of symptoms, compared with placebo, for at least six months with rotigotine, with acceptable side effects.

In the Neurology study, patients were randomly assigned to placebo (96 patients) or rotigotine (181 patients).

Rotigotine was started at a dose of 2 mg/24 hours (10-cm² patch size; 4.5-mg total drug content), titrated weekly up to 6 mg/24 hour (30-cm² patch size; 13.5-mg total drug content), and then maintained for six months.

The primary efficacy measures were change from baseline in the UPDRS parts II and III scores, and percentage of responders, defined as patients with at least a 20% improvement.

The authors found that patients receiving rotigotine had a mean absolute difference of 5.28 (+ 1.18) points lower in UPDRS subtotal scores compared with those receiving placebo (P<0.0001).

The largest contributor to the difference was the mean change in UPDRS part III motor score, which decreased by 3.50 points (+ 7.26).

Nearly half of all patients who received rotigotine (48%) had at least a 20% improvement in UPDRS score, compared with about 19% of patients on placebo (P<0.0001).

Adverse events included application-site reactions in 44% of patients on rotigotine versus 12% of those on placebo, nausea in 41% versus 17% respectively, somnolence in 33% of those on active drug versus 20% of those on placebo, and dizziness in 19% of those on rotigotine versus13% of controls.

Most of the side effects were mild or moderate in intensity. In all, 14% of patients on the active drug and 6% of those on placebo discontinued using the patch because of adverse events.

Long-Term Use of Parkinson’s Drug May Impact Vision

Parkinson’s disease, the second most common neurodegenerative disease after Alzheimer’s, is often treated with amantadine.

The drug helps alleviate patients’ motor problems and may be taken for years. Doctors have long known that amantadine treatment causes abnormal changes in the cornea in some Parkinson’s patients.

The cornea is the eye’s clear outer surface that provides most of the visual power. Usually corneal reactions occur soon after starting the drug and disappear a few weeks after it is withdrawn. But sometimes corneal disorders appear only after years of treatment, and the corneas of these patients often do not recover when amantadine is stopped.

Won Ryang Wee, MD, PhD, and his colleagues at Seoul National University College of Medicine, South Korea, studied whether the effect of amandatine on corneal endothelial cells is dependent on the cumulative dose received.

The researchers compared 169 eyes of amandatine-treated patients with an equal number of matched controls; the average age of all subjects was 59. They found that the patient group with the highest cumulative amandatine intake and/or longest duration of treatment (up to 8 years) had the most significant reductions in endothelial cell density (ECD). Endothelial cells work to keep excess water out of the main body of the cornea. When there are too few endothelial cells, corneal edema (swelling) results and vision is impaired. This study noted two early indicators of abnormal corneal changes in response to amandatine, before ECD reduction occurred: deformation of the normal hexagonal cell shape, and increase in cell size variation. The findings also show that ECD reduction in response to amandatine treatment does not occur quickly.

“Assuming other studies confirm these results, ophthalmologists and neurologists should consider evaluating a patient’s corneal endothelium at the beginning of treatment with amandatine and reassess at regular intervals if the drug is used long term,” Dr. Wee said, “and additional monitoring would be needed for patients with other conditions that reduce ECD-such as recent cataract surgery or ongoing glaucoma, uveitis or Fuch’s dystrophy-because corneal edema could develop during treatment.”

Spinal Cord Stimulation May Benefit Parkinson’s Patients

A new study from Rhode Island Hospital indicates that spinal cord stimulation may be able to modulate Parkinson’s disease symptoms.

The lead author will present the findings at the 2010 American Society for Stereotactical and Functional Neurosurgery (ASSFN) Biennial Meeting, June 14-16 in New York City.

Ming Cheng, MD, is a neurosurgeon at Rhode Island Hospital and the lead author on an abstract called “Outcome of Spinal Cord Stimulation.” Other studies previously found motor function improvement with spinal cord stimulation (SCS) in an animal model of Parkinson’s disease (PD). The findings from these studies prompted the researchers to test SCS on a single 82-year-old male with PD.

Cheng, who is also an assistant professor of neurosurgery at The Warren Alpert Medical School of Brown University, worked with colleagues at Brown to implant the SCS system and then test the effects at multiple frequencies while the patient was off medication.

“Our study shows no changes in pain assessment to control for reduction in pain as the reason for motor improvement,” says Cheng. “What we did find is that low-frequency SCS produced a readily apparent and statistically significant worsening of Parkinson’s disease symptoms.” Cheng, who is also a physician with the Neurosurgery Foundation, Inc., continues, “These findings and locomotion ‘walking time’ were reversed at high stimulation frequencies.”

This work has been replicated in a second patient, with similar results. Cheng notes that the results of the study are extremely limited as it was performed in only one patient; however, he believes that further studies are in order to determine the possible benefits of this approach for PD patients.

Drug Improves Tremors, Involuntary Movements In Parkinson Patients

A drug used to treat epilepsy has been found to significantly improve tremors, motor fluctuations, and other involuntary movements, or dyskinesias, in patients with Parkinson disease, according to a study published in the January 2, 2007, issue of Neurology, the scientific journal of the American Academy of Neurology.

The three-month, multi-center study in Japan involved 279 Parkinson disease patients who weren’t responding well to the commonly used drug, levodopa, to manage their symptoms. The patients were divided into groups that took 25, 50 or 100 mg a day of the drug zonisamide or placebo.

Researchers found at least 30 percent of patients taking zonisamide experienced a more than 30-percent reduction in their score on a rating scale used to follow the progression of a person’s Parkinson disease. The most significant improvement was seen in the group taking 50 mg of zonisamide a day. That group saw a nearly 40-percent improvement in the score.

“Zonisamide treatment improved all main Parkinson disease symptoms in these patients, including tremor and other disabling dyskinesias. This is consistent with findings from other, smaller studies,” said lead author Miho Murata, MD, PhD, with the National Center of Neurology and Psychiatry in Tokyo, Japan. “Zonisamide is safe, effective, and well tolerated at 25 to 100 mg a day as an added treatment in patients with Parkinson disease.”

While this study lasted only 12 weeks, Murata says their preliminary data shows the benefits of zonisamide observed at 12 weeks were maintained for more than a year in all 17 patients involved in a study on the long term effects of zonisamide on Parkinson disease.

Murata says it’s not fully understood yet as to why zonisamide helps Parkinson disease symptoms and further study is needed to clarify the mechanism behind the drug’s benefits.

According to the study, the drug’s most common side effects were drowsiness, apathy, weight loss, and constipation.

The study was supported by Dainippon Sumitomo Pharma, which discovered zonisamide.

Guideline Issued for Treating Sleep, Constipation, Sexual Problems in Parkinson’s Disease

The American Academy of Neurology has issued a new guideline recommending the most effective treatments to help people with Parkinson’s disease who experience sleep, constipation, and sexual problems, which are common but often underrecognized symptoms.

The guideline is published in the March 16, 2010, issue of Neurology®, the medical journal of the American Academy of Neurology.

“While the main symptom of Parkinson’s disease is movement problems, there are many other symptoms to be aware of, including sleep disorders, constipation, and problems with urination and sexual function,” said lead guideline author Theresa A. Zesiewicz, MD, with the University of South Florida in Tampa and a Fellow of the American Academy of Neurology. “Without treatment, these symptoms can cause as much pain and discomfort as movement problems and greatly affect daily routines and quality of life.”

Sexual problems often affect people with Parkinson’s disease. In men with Parkinson’s, erectile dysfunction is common. According to the guideline, the drug sildenafil citrate may improve erectile dysfunction. The guideline also found the drug isosmotic macrogol may improve constipation in people with Parkinson’s disease.

For problems with excessive daytime sleepiness, the guideline recommends that doctors consider the drug modafinil to help people feel more awake. However, it’s important to note that one study showed people taking modafinil had a false sense of alertness. This may pose a safety risk for activities such as driving. The guideline also found the drug methylphenidate may help with fatigue.

The guideline mentions two tests to help identify nonmotor symptoms of Parkinson’s disease. One is the NMSQuest rating scale. The other is the Unified Parkinson’s Disease Rating Scale (UPDRS). The original UPDRS mainly tests for movement problems. Doctors use the updated version of the UPDRS to test for all Parkinson’s symptoms, including those unrelated to movements. People with Parkinson’s disease should talk to their doctor about whether these tests may be helpful.

“More research is needed into these symptoms of Parkinson’s disease since there are still a lot of unknown answers as to what causes these symptoms and how they can best be treated to improve lives,” said Zesiewicz.

Modafinil Can Improve Physical Fatigue in Patients With Parkinson’s Disease

Modafinil can reduced physical fatigue commonly seen in patients with Parkinson’s disease, researchers reported here at the 132nd Annual Meeting of the American Neurological Association (ANA).

“It was very gratifying to find that modafinil improves physical fatigue in patients with Parkinson’s disease,” reflected study presenter Jau-Shin Lou, MD, Associate Professor of Neurology, University of Oregon Medical School, Portland, Oregon, United States.

Dr. Lou concluded that, “at the regular dose used in narcolepsy, modafinil clearly reduced physical fatigue in Parkinson’s disease.”

Dr. Lou and colleagues undertook the study because Parkinson’s disease patients at all stages of the disease are known to have physical fatigue. Studies have shown that more than half of patients with Parkinson’s experience physical fatigue. “This is a well-documented phenomenon,” he lamented.

“Modafinil is approved for narcolepsy and has been shown to improve fatigue in multiple sclerosis, so we deduced that it was worth evaluating in Parkinson’s disease,” said Dr. Lou.

In their study, the researchers assessed fatigue levels in 19 Parkinson’s disease patients using the Multidimensional Fatigue Inventory (MFI), a measurement tool that has been in use for about 20 years.

Nine patients who were on current Parkinson’s disease treatments were randomly assigned to modafinil 100 mg BID and 10 patients received placebo. Finger tapping and intermittent force generation were used to evaluate physical fatigue objectively and MFI was used to measure fatigue subjectively. Subjects completed the Epworth Sleepiness Scale (ESS), the Center for Epidemiologic Studies Depression Scale (CES-D), and the multidimensional McGill Quality of Life (MQOL).

Results showed that the modafinil group, but not the placebo group, showed increased finger tapping frequency (P <.05), increased tapping velocity (P <.05), less fatigue from finger tapping (P <.05), less general fatigue in the MFI (P <.05), less fatigue from intermittent force generation (P <.1), and less sleepiness (P <.1) from week 1 to 8. Both groups reported improved quality of life.

Dr. Lou concluded that, “at the regular dose used in narcolepsy, modafinil clearly reduced physical fatigue in Parkinson’s disease.”

He recommended that physicians prescribe modafinil to their patients with Parkinson’s disease who are suffering from fatigue.

“The agent can be used as an adjunctive medication to levodopa or a dopamine agonist,” he added.

Dr. Lou and his group hope to perform a larger trial, “but there’s no need to wait to start using modafinil,” he urged.

Parkinsonian symptoms

Dear Dr <--->,

(1) Thank you for seeing my father this coming Tuesday, 16th February 2010, for consultation on potential pharmacological intervention for my fathers Parkinsonian symptoms.

(2) Please be advised that through the assistance of Ms <---->, you will also be seeing my father the following day, on Wednesday 17th February, 2010, for botox injections for my father's body rigidity.

==========

My name is <----> and my father suffers from a broad range of Parkinson's like symptoms.  He in fact has all the cardinal symptoms of PD, but has been unresponsive to Levodopa.

I have had a very frustrating time finding help for my father, apart from Dr <---->, my father's Rehabilitation specialists, who has also tried in vain to find a Parkinson's Syndrome specialist willing to try and treat my father. The neurologists I have so far seen have only suggested Sinimet and nothing else.

I am asking for your assistance as a Neurologist specialising in movement disorders for (i) assistance in trialling other pharmacological medications that may provide some minor to moderate relief of my father's most troublesome symptoms, and assistance and guidance on botox and its potential application to assist in my father's rigidity, body pain, tremors and/or freezing.

I do understand from the out-set that my father's condition is atypical Parkinsons, and his circumstances may rule many potential treatments out. This is not an ideal case because my father does not suffer from idiopathic Parkinson's disease , but I beg you to please help us to sequentially trial some treatments that may modestly alleviate some of my fathers most inhibiting symptoms. A modest response would make a huge impact to my father's quality of life, and this is all we are expecting.  

Some important history regarding my father's condition

Overview of History

• Road Accident: April 2002 - prior to this perfect health
• Traumatic impact to top-side of head (right-side). Mid-line shift, bleeding in brain observed, fracture at base of skull. No surgical intervention.
• Induced coma for 6 days
• 6 weeks in hospital. Had to re-learn to swallow, talk and walk again.
• 2 weeks after accident started to experience Sundowner Syndrome. Significant sleeping problems.
• Improvement generally observed over next 3 years, although ongoing mobility and balance issues.
• From 2005 onwards condition started to slowly deteriorate.
• From about 2006, Parkinson's like symptoms became visible. These were noted by medical specialist as far back as 2005, although they were quite subtle back then.
• Over past 6 months, rapid increase in severity of symptoms.

Symptoms

The two most problematic symptoms are;

(1) Mobility problems, comprising:
1.        General weakness in leg muscles
2.        Rigidity in muscles, most noticeably calf muscles, neck muscles and trunk of body.
3.        Stiffness and pain in calf muscles. Experiences ongoing pain in calf and waist/abdomen/lower back
4.        Slowness in movement
5.        Freezing, especially in left leg when attempting to take first step
6.        Festinated pace of walking
7.        Shuffling of feet (small dragging steps)
8.        Gait - pronounced leaning forward and head down
9.        Impaired balance - cannot gauge back and forth movement
10.        No arm movement when walking

(2) Cognitive issues
1.         Increasing loss of mental alertness
2.         Increasing forgetfulness
3.         Increasing paranoia
4.         General confusion
5.         Orientation , gets lost within house
6.         Frequently losing track of a word or thought

(2) Faecal Inconsistence
1.        Lately can happen up to 3 times a day.
2.        Is not aware of urge until just before it happens.


(3) Other symptoms which are problematic, but not as disruptive as above two
1.        Left hand resting tremor (has been steadily increasing over past few years)
2.        Loss of strength, nimbleness and dexterity in hands
3.        Very low speaking voice- strangulation episodes at night
4.        Urinary incontinence
6.        Drooling - Saliva drooping from lip
7.        Micrographia
8.        Toned down facial expressions
9.        Frequent nightmares involving body movements. Believes that he stops breathing during night.


Attempted Treatments

July-2008 - Levodopa - duration: about 7 days - dosage from 400mg to 600mg per day. Stopped due to worsening of symptoms and hallucintions.

April-2009 - Artane 2 mg- 7 days duration - half tab per day. Stopped due to worsening of symptoms and cognitive issues.

Dec-2009 - Sinimet 100/25 - half a tab to one tab - duration only 3 days. Stopped due to worsening symptoms

Oct-2009 to Current - Two by 5 minutes of whole body vibration - no detected improvement in symptoms.

Jan-2010 - Nicotine Therapy (patches) - from 7mg to 21 mg over 24 hrs. Initial 7mg had immediate improvement for 5 days. No response since then despite increase in dosage, but 21mg seems to have created sleep disturbance.


Trial of cardilopa-levodopa never reaches some recommended therapeutic doses because of issue of tolerability

,

Thank you for agreeing to see my father on the 10th December, 2009. We look forward to seeing you then.

I hereby supply some further information to you prior to the appointment (along with a few suggestions and questions).

I hope you can take my suggestions as my effort at providing further information, rather than my trying to make medical decisions or pre-empt your expert advise. I hope you understand.

• You should by now have received a referral letter from Dr xxxxxxn (Rehabilitation Specialist, xxxxxx Hospital) with a clinical background of my father's situation. This letter was originally sent to Dr xxxt who was not available to see my father this year.

If you have not received this letter please advise me. If you have, could you please advise if this letter is sufficient as a referral letter?

• Although my father had previously tried Sinimet, due to a number of factors I do not believe that we tested this drug thoroughly.

With your agreement and support, I was hopeful that another attempt with Sinimet would be worth a try, at least as a first attempt, maybe for a longer duration, higher ultimate dosage, and/or in combination with other newly developed agonists or other ldopa enhancers.    

• Four days after the appointment with you, we will be seeing Dr xxxxx for botox injections. One area that I am not certain about (although I have yet to discuss with Dr xxxxx), is whether botox may be appropriate to alleviate the stiffness in the trunk of my father's body.

I have already discussed with Dr xxxx the (i) stiffness in my father's calfs, the (ii) lower back pain my father has, and possibly the (iii) pain my father feels in the soles of his feet.

I however do not know whether botox can help with the generalised dystonia my father experiences in the trunk of his body and neck.

If it is possible, I would value any suggestions that you may have on the sites of administration of botox to assist in my father's tense muscles across his body.

• Please note that we are realistic about the progressiveness of my father's condition, and we are merely seeking some improvement in my father's Parkinson's like symptoms. Even a small improvement would make a big difference in my father's quality of life.

PS. I will bring with me the various brain scans that were taken subsequent to my father's head injury, and any other reports I may have. Please feel free to ask me for these if they will help in your assessment on the day.



##refer to surgical intervention for urinary tract scarring

With thanks


##At the very least, my father's case would be a remarkable case study highlighting an indisputable link between direct and catastrophic head trauma and the development of of post-traumatic parkinsonism.

I am writing to you after having read about you on the web, and after having heard about your well received speeches for a Parkinson's xxx support group on the pharmacological treatment of PD.

I would also add that if there is any possibility, my father would probably greatly benefit from a multi-disciplinary approach, given what looks like the onset of (i) depression, (ii) modest cognitive decline and the contra-indications of treating these conditions along with my father's advancing age.