Sinemet shortage in early 2011?

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Those of you who take Sinemet may be interested in this news relayed by the National Parkinson’s Foundation…

The “issue” with taking the generic form of Sinemet is that the FDA requires the bioequivalence of any generic product to be between 80% and 125% of that of the innovator product. This is a rather large range.

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Email from National Parkinson’s Foundation
1/7/11

Merck & Co. Inc. has informed the Parkinson’s disease community that in early 2011, there may be a potential temporary supply shortage in the U.S. for SINEMET® (carbidopa-levodopa) and SINEMET CR® (carbidopa-levodopa controlled release tablets).

While there is currently no shortage, it is advisable to speak with your health care provider about appropriate steps should a shortage occur. Your health care provider can give you relevant information about potential short-term alternative therapies, including the availability of alternative generic equivalents.

The FDA has shown generic SINEMET® to be effective against the symptoms of Parkinson’s disease, but dosing may need to be slightly adjusted due to differences in manufacturing and formulation. Should you need to temporarily switch to a generic version of SINEMET®, be aware that some people may experience a change in how the medication works. If you do experience a change, contact your health care provider who may prescribe a different dose or timing regimen.

Patients, caregivers and health care professionals in the U.S. who have more questions about the availability of SINEMET® can contact the Merck National Service Center at 1-800-NSC-MERCK.

NPF is committed to keeping you informed of developments on this issue. We will alert you if we get any more information about either a shortage developing or the crisis being averted. If you are informed by your doctor or pharmacist that SINEMET® is not available in your area, please contact us at 1-800-4PD-INFO (473-4636) or [email protected]. If you have any questions, Dr. Okun is prepared to address issues about the shortage and generic substitution on our Ask the Doc online discussion forum.

In vivo comparison of the two most common PSP types

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This looks like a carefully-done study for 23 PSP patients though I don’t think there’s pathological confirmation of the diagnosis. Of the 23, 14 had the Richardson’s syndrome (RS) type of PSP, called “classic PSP.” Nine had PSP-parkinsonism, the second most common type of PSP.

Previous studies suggest “that the clinical presentation of the two subtypes differs especially in the first 2 years of disease and then converges.” This German study attempted to confirm that view.

They found that “RS and PSP-P show considerable symptoms overlap during the disease course when using routine assessments, with persisting differences regarding non-motor symptoms.” Those non-motor symptoms include psychological, cognitive, and behavioral deficits.

We can glean two other points from the abstract:

* “RS patients showed shorter time from disease onset to diagnosis…”

This is certainly because RS patients have “classic PSP” so neurologists are better able to recognize it as being PSP.

” Shorter disease duration of the comparably affected RS patients indicates that this subtype has an accelerated disease progression at early disease stages.”

We know from previous studies that those with the RS type of PSP have a shorter survival time than those with the PSP-P type.

Robin

Journal of Neural Transmission. 2011 Jan 5. [Epub ahead of print]

In vivo comparison of Richardson’s syndrome and progressive supranuclear palsy-parkinsonism.

Srulijes K, Mallien G, Bauer S, Dietzel E, Gröger A, Ebersbach G, Berg D, Maetzler W.
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany

Abstract
Richardson’s syndrome (RS) and progressive supranuclear palsy-parkinsonism (PSP-P) are the most common subtypes of PSP.

Post-mortem data suggests that the clinical presentation of the two subtypes differs especially in the first 2 years of disease and then converges. This hypothesis has, to our knowledge, never been confirmed in a living cohort.

Medical history was used to define subtypes retrospectively in 23 consecutive PSP patients from our outpatient clinic specialized in movement disorders. 14 patients suffered from RS, and 9 from PSP-P.

Using a prospective cross-sectional approach, clinical, cognitive, behavioral, speech and biochemical (cerebrospinal fluid tau levels) features were compared.

RS patients showed shorter time from disease onset to diagnosis and more neuropsychological and neurobehavioral deficits than PSP-P patients, but differed not significantly with regard to clinical and biochemical features.

RS and PSP-P show considerable symptoms overlap during the disease course when using routine assessments, with persisting differences regarding non-motor symptoms.

Shorter disease duration of the comparably affected RS patients indicates that this subtype has an accelerated disease progression at early disease stages.

PubMed ID#: 21207078

First AD patient with PIB scans

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Those of you interested in advances in imaging for neurodegenerative disorders and the correlations between imaging studies (while a patient is alive) and brain pathology (seen on post-mortem autopsy) will LOVE this news.

The PET is a type of brain scan. Currently, nearly all PET scans employ FDG, which picks up on glucose in the brain. For the last several years, the latest in PET scans for Alzheimer’s or other dementia patients employs PIB, Pittsburgh Compound B. PIB picks up on amyloid plaques. (The dye is retained by the insoluble amyloid protein.) Alzheimer’s disease is a disorder of two proteins — amyloid (which forms plaques) and tau (which forms tangles).

Hopefully, one day, we’ll have PET scans that can detect tau tangles (which would help diagnose PSP and CBD). Also, PSP and CBD can co-occur with Alzheimer’s Disease, so this news may be relevant to some in the PSP/CBD community also. (I’ve forgotten the exact percentage but it’s something like 20-30% of the time.)

The Alzheimer Research Forum has a (mostly-understandable) summary of a recently published article in the December 13th issue of the journal Brain about a woman with Alzheimer’s Disease who “volunteered for the first PET-PIB scan ever performed. She received another PIB scan two years later, and over the course of her disease also got an MRI and three PET scans using fluorodeoxyglucose (FDG), a marker for glucose use and therefore brain metabolism.” The woman died at the age of 61. She donated her brain for autopsy.

“Over the eight years she was studied, the woman’s score on the Mini-Mental State Examination declined from a near-normal score of 27 down to five. The FDG data showed that her brain’s glucose metabolism decreased in parallel with her cognitive powers. By contrast, PIB retention, already high at first examination, showed little change over two years during which her cognition declined steeply. The amount of amyloid deposition seen at autopsy three years later also looked similar to PIB estimates…suggesting no further change in amyloid between the second PIB scan and death three years later. This pattern matches the data from numerous previous studies, in which PIB retention increases during mild cognitive impairment, then seems to plateau during AD.”

“Autopsy results confirmed the patient’s diagnosis of pure AD. … The results confirmed that in vivo PIB retention correlates quite well with amyloid deposits, but does not correlate closely with tau and neurofibrillary tangles, as previous studies have found. … In addition, the authors performed detailed studies not done before and turned up intriguing correlations between amyloid accumulation and synaptic receptor density, as well as a surprising lack of correlation with markers of inflammation.”

The summary on the Alzheimer Research Forum discusses four clinical trials with compounds targeting amyloid in Alzheimer’s patients. The trials were all negative. This PET-PIB study gives additional insight as to why that may be the case.

Here’s the summary on ARF about the recently-published study:
http://www.alzforum.org/new/detail.asp?id=2653

Note that some of the comments are well worth reading, though harder to understand than the summary. Some of the comments (posted in 2004) give historical info on PIB.

The recently-published study is available at no charge through the journal Brain. See:
http://brain.oxfordjournals.org/content/134/1/301.long (for HTML version)

Eye movement disturbances

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I struggled with some of this abstract although the topic is very interesting — how eye movements are affected in PSP, what this means about where in the brain PSP might originate, and how this may help diagnose PSP and disorders that mimic PSP.

Here is one point I could grasp:

“Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free.”

Robin

Frontiers in Neurology. 2010 Dec 3;1:147.

The disturbance of gaze in progressive supranuclear palsy: implications for pathogenesis.

Chen AL, Riley DE, King SA, Joshi AC, Serra A, Liao K, Cohen ML, Otero-Millan J, Martinez-Conde S, Strupp M, Leigh RJ.
Veterans Affairs Medical Center, University Hospitals Case Medical Center, Cleveland, OH.

Abstract
Progressive supranuclear palsy (PSP) is a disease of later life that is currently regarded as a form of neurodegenerative tauopathy. Disturbance of gaze is a cardinal clinical feature of PSP that often helps clinicians to establish the diagnosis. Since the neurobiology of gaze control is now well understood, it is possible to use eye movements as investigational tools to understand aspects of the pathogenesis of PSP.

In this review, we summarize each disorder of gaze control that occurs in PSP, drawing on our studies of 50 patients, and on reports from other laboratories that have measured the disturbances of eye movements. When these gaze disorders are approached by considering each functional class of eye movements and its neurobiological basis, a distinct pattern of eye movement deficits emerges that provides insight into the pathogenesis of PSP.

Although some aspects of all forms of eye movements are affected in PSP, the predominant defects concern vertical saccades (slow and hypometric, both up and down), impaired vergence, and inability to modulate the linear vestibulo-ocular reflex appropriately for viewing distance. These vertical and vergence eye movements habitually work in concert to enable visuomotor skills that are important during locomotion with the hands free.

Taken with the prominent early feature of falls, these findings suggest that PSP tauopathy impairs a recently evolved neural system concerned with bipedal locomotion in an erect posture and frequent gaze shifts between the distant environment and proximate hands. This approach provides a conceptual framework that can be used to address the nosological challenge posed by overlapping clinical and neuropathological features of neurodegenerative tauopathies.

PubMed ID#: 21188269 (see pubmed.gov for this abstract only)

MSA – Current and Future Treatments

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This medical journal article on current and future approaches to the management of MSA was published in July 2010 but the abstract was just recently posted to PubMed.  The article reviews current symptomatic treatment, potential neuroprotective drugs, and future approaches to the management of MSA.  It was written by a French team of neurologists.

Wonderfully, the full article is available at no charge online via PubMed:

www.ncbi.nlm.nih.gov/pmc/articles/PMC3002658/

Therapeutic Advances in Neurological Disorders. 2010 Jul;3(4):249-63.
Multiple system atrophy: current and future approaches to management.
Flabeau O, Meissner WG, Tison F.
Department of Neurology, University Hospital of Bordeaux, Bordeaux, France.

Here are a few notes:

CURRENT TREATMENT

There is a nice table (Table 1) of current first-line treatment for various symptoms and alternative treatments.  I thought one symptom made no sense to include and its treatment also made no sense:  the treatment for “cognitive impairment” is “speech therapy.”  Table 1 is a good summary of all the first half of the article.  In the article, it seems that what is meant by “cognitive impairment” is “verbal fluency”; I’m unclear if speech therapy will help with verbal fluency.

Here’s a very short summary of the current treatments:

“Current symptomatic management in MSA should target motor impairment, autonomic failure and depression, as these features are associated with a poor quality of life. Levodopa remains the main treatment for MSA, despite its modest and nonsustained effect. Among the several treatments available for OH, only midodrine meets the criteria of evidence-based medicine. Strategies for urinary disorders are well standardized, while other symptoms such as breathing disorders, RBD, depression or dystonia remain out of consensus.”

Here are some things I learned from the current treatment section of the article:

* “Although levodopa induces less delirium and hallucinations in MSA than in PD, it can lead to adverse effects such as … pathological hypersexuality.”

I hear from many PD caregivers about Sinemet causing hypersexuality but I’ve never heard this from MSA caregivers.

* “According to consensus criteria, levodopa unresponsiveness should only be accepted after a treatment with at least 1 g of levodopa per day for at least 3 months.”

* “Clean intermittent self- catheterization (CISC) is recommended as the first-line treatment when the postvoid residual is above 100 ml. Thus, the residual volume should be regularly monitored, for example with a portable ultrasound device. The critical threshold of 100 ml is reached in a mean of 2 years after disease diagnosis.”

* “To reduce the risk of infection due to permanent catheterization, surgery such as sphincterotomy or sphincteric wall stenting can be considered as a last option in MSA” [for the treatment of urinary incontinence].

* RBD (REM sleep behavior disorder) “is observed in 69-100% of systematic polysomnography recordings in MSA patients.”

NEUROPROTECTIVE STRATEGIES

All clinical trials investigating neuroprotective strategies — riluzole, minocycline, growth hormone, and estrogen (tested in MSA-C only) — have failed to show any disease-modifying benefits.  The authors advocated for further trials of growth hormone at higher doses and with more patients.

FUTURE THERAPIES

For neuroprotection, several drugs are being tested in MSA:  lithium, rasagiline, and intravenous immunoglobulins.  The lithium study is taking place in Italy.  The rasagiline (Azilect) trial has been going on in the US for a year or more.

The IVIg trial is going on at the University of Massachusetts (Peter Novak, MD, PhD is the principal investigator).  The authors say:  “a former clinical report [on IVIg] does not support any therapeutic effect in MSA.”

The authors mention rifampicin (“no human trial has been yet planned”) and NSAIDs (“the harmful adverse effects of long-term use may limit their evaluation until the development of safer drugs”).

For neurorestoration, three treatments are described:
* transplantation of fetal dopaminergic cells
* injection of bone marrow mesenchymal stem cells
* injection of granulocyte colony stimulating factor (GCSF)

In the “Future Therapies” section, the authors discuss the importance of researching unexplained sudden death in MSA. The authors say:  “Occurrence of sudden death is a common cause of mortality in MSA and may happen in the early stages while disability remains acceptable. The origin of sudden death in MSA remains unknown, although clinical reports, experimental and neuropathological evidence suggest that respiratory dysfunction may be the leading cause.”

The importance of the clinical diagnostic criteria and biomarkers is discussed.

Robin