ScienceDaily (Dec. 17, 2008) — A new study shows that antidepressant drugs which only affect serotonin, often used as first choice treatments, may not be best for depression in people with Parkinson's disease. The new research is published in the December 17, 2008, online issue of Neurology®, the medical journal of the American Academy of Neurology. Depression affects up to 50 percent of people with Parkinson's disease.
The study is the first to compare an older antidepressant that targets two receptors in the brain with a newer generation serotonin only-based drug and placebo. It is also the largest placebo-controlled study for Parkinson's disease depression.
In the study, scientists gave 52 people diagnosed with Parkinson's disease and depression either nortriptyline, a tricyclic antidepressant (TCA), paroxetine CR, a selective serotonin reuptake inhibitor (SSRI) or a placebo pill. Tricyclics affect both norepinephrine and serotonin, two different receptors in the brain. The people were tested for improvement of depression symptoms at two, four and eight weeks after starting treatment.
The study found that the people who took nortriptyline were nearly five times more likely to see improvement in depression symptoms when compared with the people who took paroxetine CR.
"I think that this study shows a number of important things. First, that people with Parkinson's disease can respond to antidepressants. This is important because depression in Parkinson's disease is underrecognized, underappreciated and undertreated. Commonly, the attitude is, of course you're depressed, you have a serious illness. This study shows that patients should have hope that they can be helped," said study author Matthew Menza, MD, a Professor of Psychiatry and Neurology with UMDNJ-Robert Wood Johnson Medical School in Piscataway, NJ. "Second, the study suggests that we may need to use medications that affect both serotonin and norepinephrine, not just serotonin, in the brain to be successful in treating depression related to Parkinson's disease."
Menza also says that in addition to the older antidepressant, nortriptyline, that was tested in the study, there are newer mediations that affect both serotonin and norepinephrinem, and these need to be tested.
Tricyclic antidepressants are one of the older classes of antidepressants and have been used since the 1950s. Tricyclics have an increased risk of overdose and death due to toxic effects on the heart and brain. "People on a tricyclic antidepressant should have their dosages monitored closely by their doctor," said Menza.
The study was supported by the National Institute for Neurological Disorders and Stroke (NINDS).
Adapted from materials provided by American Academy of Neurology.
Saturday, December 27, 2008
Tuesday, December 16, 2008
* Types of Cognitive Problems You Might Expect in PD Cases
Parkinson’s disease aka PD is often viewed as a chronic illness that affects motor coordination only. However, doctors are increasingly recognizing that other problems are also manifested as well such as cognitive impairment. Thought processes, memory, attention span and memory alterations are a part of PD. For the most part, most treatments for the disease focus on motor skill improvement; therefore, the cognitive problems sometimes are ignored or not treated.
Predominance of Cognitive Problems
If you are looking to understand cognition, it is a broad term that is used to categorize a number of mental abilities, namely the brain’s ability to process, store and utilize information. Attention span, memory, language, conceptual thinking, concrete problem solving and even visual perception are all involved areas of cognitive thinking. It is important to note that virtually all people with Parkinson’s disease will experience some type of interruption in cognitive function and can range from minor issues to more severe problems.
You may consider a cognitive impairment as a minor inconvenience while another may experience issues severe enough to impact quality of life. Dementia is classified as a cognitive impairment and this involves several interruptions in the cognitive area. Some Parkinson’s patients may have mild motor coordination problems but have dementia which calls for supervised living while others may not develop dementia until the latest stages of Parkinson’s.
Cognitive difficulties are often classified in different areas so that experts can better identify ways to help. It is important to note that your general intelligence and memories acquired before PD usually stay with you. If you develop a cognitive issue, memories and skills learned after PD cognitive symptoms are displayed could be lost and have to be relearned. Here are a few examples of cognitive dysfunction:
* Memory interruption ñ If you have already learned certain information, it is not uncommon to forget something or how to do it without memory cues. When you have PD, having visual cues helps to retain information as well as repetition, especially if you want to recall that information later.
* Executive dysfunction ñ This is a broad term that covers problem solving, project planning and other mental acrobatic tasks. Freezing mid-task is common so it is important for PD patients to focus on one thing at a time.
* Attention deficit ñ Not quite like ADD, in PD patients, there is a problem with attention. It is best to focus on one thing at a time as multi-tasking can cause problems. For instance, PD patients may find it hard to take a leisurely walk and talk with a companion at the same time. Even listening to music and walking can be an issue.
* Slowed cognitive function ñ Sometimes the ability to retrieve memories or process information that pertains to a problem can be an issue with PD patients. This condition called bradyphrenia can cut short your independence, especially in the workplace.
Memory devices and visual cues are the best things that can prompt your memory should cognitive function become an issue. In addition, some doctors are prescribing medications used on Alzheimer’s patients in the hopes it can slow down the progression of the disease or stop it all together, at least cognitive-wise.
Predominance of Cognitive Problems
If you are looking to understand cognition, it is a broad term that is used to categorize a number of mental abilities, namely the brain’s ability to process, store and utilize information. Attention span, memory, language, conceptual thinking, concrete problem solving and even visual perception are all involved areas of cognitive thinking. It is important to note that virtually all people with Parkinson’s disease will experience some type of interruption in cognitive function and can range from minor issues to more severe problems.
You may consider a cognitive impairment as a minor inconvenience while another may experience issues severe enough to impact quality of life. Dementia is classified as a cognitive impairment and this involves several interruptions in the cognitive area. Some Parkinson’s patients may have mild motor coordination problems but have dementia which calls for supervised living while others may not develop dementia until the latest stages of Parkinson’s.
Cognitive difficulties are often classified in different areas so that experts can better identify ways to help. It is important to note that your general intelligence and memories acquired before PD usually stay with you. If you develop a cognitive issue, memories and skills learned after PD cognitive symptoms are displayed could be lost and have to be relearned. Here are a few examples of cognitive dysfunction:
* Memory interruption ñ If you have already learned certain information, it is not uncommon to forget something or how to do it without memory cues. When you have PD, having visual cues helps to retain information as well as repetition, especially if you want to recall that information later.
* Executive dysfunction ñ This is a broad term that covers problem solving, project planning and other mental acrobatic tasks. Freezing mid-task is common so it is important for PD patients to focus on one thing at a time.
* Attention deficit ñ Not quite like ADD, in PD patients, there is a problem with attention. It is best to focus on one thing at a time as multi-tasking can cause problems. For instance, PD patients may find it hard to take a leisurely walk and talk with a companion at the same time. Even listening to music and walking can be an issue.
* Slowed cognitive function ñ Sometimes the ability to retrieve memories or process information that pertains to a problem can be an issue with PD patients. This condition called bradyphrenia can cut short your independence, especially in the workplace.
Memory devices and visual cues are the best things that can prompt your memory should cognitive function become an issue. In addition, some doctors are prescribing medications used on Alzheimer’s patients in the hopes it can slow down the progression of the disease or stop it all together, at least cognitive-wise.
Friday, December 12, 2008
Treatment Helps Parkinson's Patients Talk Clearly
Reported by: Mary King
Wednesday, Dec 10, 2008 @01:03pm EST
HAGERSTOWN - A new treatment in Washington County aims to break down the communication barrier for Parkinson's disease patients.
Carolyn Reed was diagnosed with Parkinson’s disease ten years ago, but it wasn’t until recently that her illness made talking a challenge.
"I could hear them but they couldn't hear me," she said.
Pathologists say it's is common obstacle for Parkinson’s patients. It's called - disarthrea. A patient's speech can become softer and harder to understand.
Speech language pathologist Kymberli Dixon says, "It's difficult for them to be able to gage the amount of loudness or effort that's required for them to be understood at a normal conversational level."
The hardest part for Carolyn Reed was that no one, not even her husband, could understand her, but when she came here to total rehab care all of that changed.
"You're talking about one month of treating a patient and seeing a life change in 4 weeks," Dixon said.
The results were achieved using the Lee Silverman Voice Treatment, a therapy that has been around for years but remains hard to find because therapists must be certified.
Carolyn was the guinea pig at Washington County Hospital. Therapists used a sound pressure level meter to gauge how loud Carolyn was talking and progressively brought her voice back.
Carolyn's daughter, Alys Dahbura, said, "I don't have to ask her as often to speak up or repeat herself."
Two other patients have completed the program in Washington County. They're back to doing things they never thought they'd do again. For Carolyn, that includes reading to her granddaughter
Carolyn's also using her new found voice to spread the news about the treatment.
Wednesday, Dec 10, 2008 @01:03pm EST
HAGERSTOWN - A new treatment in Washington County aims to break down the communication barrier for Parkinson's disease patients.
Carolyn Reed was diagnosed with Parkinson’s disease ten years ago, but it wasn’t until recently that her illness made talking a challenge.
"I could hear them but they couldn't hear me," she said.
Pathologists say it's is common obstacle for Parkinson’s patients. It's called - disarthrea. A patient's speech can become softer and harder to understand.
Speech language pathologist Kymberli Dixon says, "It's difficult for them to be able to gage the amount of loudness or effort that's required for them to be understood at a normal conversational level."
The hardest part for Carolyn Reed was that no one, not even her husband, could understand her, but when she came here to total rehab care all of that changed.
"You're talking about one month of treating a patient and seeing a life change in 4 weeks," Dixon said.
The results were achieved using the Lee Silverman Voice Treatment, a therapy that has been around for years but remains hard to find because therapists must be certified.
Carolyn was the guinea pig at Washington County Hospital. Therapists used a sound pressure level meter to gauge how loud Carolyn was talking and progressively brought her voice back.
Carolyn's daughter, Alys Dahbura, said, "I don't have to ask her as often to speak up or repeat herself."
Two other patients have completed the program in Washington County. They're back to doing things they never thought they'd do again. For Carolyn, that includes reading to her granddaughter
Carolyn's also using her new found voice to spread the news about the treatment.
Sunday, December 7, 2008
Drug Treatment For Parkinson's Disease Can Help Confirm Suspected Diagnosis, Neurologist Says
ScienceDaily (Dec. 3, 2008) —
Levodopa has long been proven to provide the greatest relief of all available medications in the treatment of Parkinson's disease. It also is the most cost-effective drug for managing the full range of problems associated with this chronic neurological disorder, which affects an estimated one million Americans.
In the Dec. 4 issue of the New England Journal of Medicine, Henry Ford Hospital neurologist Peter A. LeWitt, M.D., writes that levodopa should be used not only for treating both early and advanced stages of Parkinson's disease, but also for confirming a suspected diagnosis of Parkinson's disease.
"Within a few minutes after taking an oral dose of levodopa, a patient can recover from previous impairments in speech, dexterity and gait," says LeWitt. "Though the start of levodopa can be postponed if the clinical manifestations of Parkinson's disease are mild and tolerable, it may be the only effective option to control discomfort and disability even for mildly affected patients."
Affecting 1 to 2 percent of the population over the age of 60, Parkinson's disease is a degenerative disorder of the central nervous system that causes tremors and impairs a person's motor skills, speech, balance and posture. Its cause is unknown, but many clues are guiding clinical trials.
A small region deep within the brain is the source for the symptoms of Parkinson's disease. When brain neurons in this part of the brain begin to die, these cells can no longer manufacture the molecule dopamine, a chemical critical for controlling movement. Levodopa replaces the deficient dopamine, reversing most features of Parkinson's disease.
Among patients with Parkinson's disease, the pace and extent of progression in neurologic deficits can greatly vary. The burden on quality of life spans a wide spectrum too, Dr. LeWitt says, from minimal discomfort and disability to marked impairment of capabilities such as independence, safety and communication.
While it is shown to improve motor impairments, levodopa often does not provide relief from the tremors and can cause involuntary movements and other side effects, requiring physicians to carefully re-assess the treatment regimen.
In the first few weeks of use, the dose of levodopa given to the patient may need to be adjusted to achieve maximum benefit. Over time, levodopa dosing often needs to be tailored to a patient's needs, sometimes in combination with other medications to optimize its effects.
"Although available controlled-release preparations are designed for more extended drug delivery, they generally do not achieve the same effects as immediate-release tablets taken closer together," writes Dr. LeWitt.
Journal reference:
1. LeWitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med, 2008; 359: 2468-2476
Adapted from materials provided by Henry Ford Health System, via EurekAlert!, a service of AAAS.
Henry Ford Health System (2008, December 3). Drug Treatment For Parkinson's Disease Can Help Confirm Suspected Diagnosis, Neurologist Says. ScienceDaily. Retrieved December 7, 2008, from http://www.sciencedaily.com /releases/2008/12/081203184405.htm
Levodopa has long been proven to provide the greatest relief of all available medications in the treatment of Parkinson's disease. It also is the most cost-effective drug for managing the full range of problems associated with this chronic neurological disorder, which affects an estimated one million Americans.
In the Dec. 4 issue of the New England Journal of Medicine, Henry Ford Hospital neurologist Peter A. LeWitt, M.D., writes that levodopa should be used not only for treating both early and advanced stages of Parkinson's disease, but also for confirming a suspected diagnosis of Parkinson's disease.
"Within a few minutes after taking an oral dose of levodopa, a patient can recover from previous impairments in speech, dexterity and gait," says LeWitt. "Though the start of levodopa can be postponed if the clinical manifestations of Parkinson's disease are mild and tolerable, it may be the only effective option to control discomfort and disability even for mildly affected patients."
Affecting 1 to 2 percent of the population over the age of 60, Parkinson's disease is a degenerative disorder of the central nervous system that causes tremors and impairs a person's motor skills, speech, balance and posture. Its cause is unknown, but many clues are guiding clinical trials.
A small region deep within the brain is the source for the symptoms of Parkinson's disease. When brain neurons in this part of the brain begin to die, these cells can no longer manufacture the molecule dopamine, a chemical critical for controlling movement. Levodopa replaces the deficient dopamine, reversing most features of Parkinson's disease.
Among patients with Parkinson's disease, the pace and extent of progression in neurologic deficits can greatly vary. The burden on quality of life spans a wide spectrum too, Dr. LeWitt says, from minimal discomfort and disability to marked impairment of capabilities such as independence, safety and communication.
While it is shown to improve motor impairments, levodopa often does not provide relief from the tremors and can cause involuntary movements and other side effects, requiring physicians to carefully re-assess the treatment regimen.
In the first few weeks of use, the dose of levodopa given to the patient may need to be adjusted to achieve maximum benefit. Over time, levodopa dosing often needs to be tailored to a patient's needs, sometimes in combination with other medications to optimize its effects.
"Although available controlled-release preparations are designed for more extended drug delivery, they generally do not achieve the same effects as immediate-release tablets taken closer together," writes Dr. LeWitt.
Journal reference:
1. LeWitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med, 2008; 359: 2468-2476
Adapted from materials provided by Henry Ford Health System, via EurekAlert!, a service of AAAS.
Henry Ford Health System (2008, December 3). Drug Treatment For Parkinson's Disease Can Help Confirm Suspected Diagnosis, Neurologist Says. ScienceDaily. Retrieved December 7, 2008, from http://www.sciencedaily.com /releases/2008/12/081203184405.htm
Tuesday, December 2, 2008
Management of Dyskinesias in Parkinson Disease
Professor Yasser Metwally
November 19, 2008 — Dyskinesias, along with motor fluctuations, are the main motor complications of levodopa therapy. A retrospective analysis of studies investigating incidence of dyskinesias with levodopa treatment estimated that slightly more than one third of patients who had PD had dyskinesias after 4 to 6 years [1]. Early-onset PD and higher doses of levodopa are the biggest risk factors for the development of dyskinesias [2,3]. Dyskinesias may affect any part of the body and can be choreic or dystonic. They may manifest when plasma levodopa levels are at their peak (peak-dose dyskinesias), as plasma levodopa levels are rising and falling (diphasic dyskinesias), or when plasma levodopa levels are low (off-state dystonia). Dyskinesias typically are mild but may interfere with quality of life when painful or severe, as seen in advanced PD [4].
One way of treating dyskinesias is to modify the antiparkinsonian regimen. Peak-dose dyskinesias are related directly to the amount of levodopa given per dose, so decreasing individual doses generally reduces dyskinesias. The amount of clinical benefit to motor symptoms in PD may decline, however, and patients may experience increasing “off” periods. Thus, a decrease in individual doses of levodopa often has to be combined with more frequent administration, a practice termed dose fractionation. There are significant limitations to this approach, however, which are detailed in the article by Dewey elsewhere in this issue. Discontinuing catechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase (MAO)-B inhibitors also may be helpful in reducing peak-dose dyskinesias.
Sustained-release formulations in theory could reduce dyskinesias, as they are released slowly throughout the day. In practice, however, they tend to prolong the duration of dyskinesias and increase the severity of dyskinesias in the late afternoon or early evening [5]. Patients who have dyskinesias and are on sustained-release levodopa formulations may benefit from switching to immediate-release levodopa.
Diphasic dyskinesias can be difficult to treat. The same strategies can be tried, but there are no data to support one strategy over the other. Other options include overlapping the doses of levodopa to prevent trough plasma levodopa levels until late in the evening or administering very small doses of levodopa frequently (such as 50 mg of levodopa given hourly while awake) [6].
Strategies for treating off-state dystonias are similar to strategies to reduce motor fluctuations in PD and may include changing the levodopa dosing schedule or adding dopamine agonists, COMT inhibitors, or MAO-B inhibitors.
Recent evidence-based reviews recommend amantadine for treating dyskinesias in PD [7,8]. Amantadine is believed to have an antidyskinetic effect through its action at the N-methyl-D-aspartate receptor. Amantadine can reduce dyskinesias between 24% and 60% [9,10,11,12,13]. In one study, the effect of amantadine was maintained for up to a year. Some patients, however, are reported to have had rebound dyskinesias when amantadine was discontinued [12]. Side effects include confusion, peripheral edema, and livedo reticularis.
A double-blind, placebo-controlled trial of clozapine demonstrates an increase in “on” time without dyskinesias with a corresponding decrease in “on” time with dyskinesias [14]. The potential for agranulocytosis and the frequent blood monitoring required make it an unattractive agent, however. Buspirone is reported effective in one small crossover trial of 10 patients [15], but only seven patients completed the trial, and there are no other large randomized studies. Clinical trials of other drugs reported to be helpful for treating dyskinesias were uncontrolled or failed to show efficacy in large double-blind trials [6,16].
Although pallidotomy commonly was used as a surgical intervention for dyskinesias with good results [8], most surgical centers have turned to deep brain stimulation (DBS) to treat patients who have motor fluctuations and dyskinesias. There are two main targets for DBS in patients who have PD: the globus pallidus interna (GPi) and the subthalamic nucleus (STN). Although DBS of the GPi reduces dyskinesias in open-label reports and blinded evaluations of patients on and off stimulation [17,18], a recent practice parameter determined that there was insufficient evidence to determine the efficacy of GPi DBS for dyskinesias [7]. Part of this lack of evidence is because most centers prefer to place electrodes in the STN DBS. In a meta-analysis of outcomes, STN DBS reduced dyskinesias in patients who had PD by an average of 69.1% [19]. This occurs along with a reduction in levodopa dosage, which is mainly responsible for the improvement in dyskinesias. Based on existing studies, STN DBS is considered possibly effective for reducing motor fluctuations, dyskinesias, and antiparkinsonian medications in PD [7]. Adverse effects from DBS surgery may include surgical complications, such as hemorrhage, stroke, infection of the device, seizures, delirium, and stimulation-related effects, such as dystonia, confusion, paresthesias, dysarthria, and diplopia, depending on the stimulation site.
References
1. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16:448-458.
2. Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol. 2006;5:355-363.
3. Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol. 1999;246:1127-1133.
4. Pechevis M, Clarke CE, Vieregge P, et al. Effects of dyskinesias in Parkinson’s disease on quality of life and health-related costs: a prospective European study. Eur J Neurol. 2005;12:956-963.
5. Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa-induced dyskinesias. Mov Disord. 2007;22:1379-1389quiz 1523.
6. Muenter MD. Patterns of dystonia in response to L-Dopa therapy for Parkinson’s disease. Mayo Clin Proc. 1977;52:163-174.
7. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66:983-995.
8. Goetz CG, Poewe W, Rascol O, et al. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to 2004. Mov Disord. 2005;20:523-539.
9. Luginger E, Wenning GK, Bosch S, et al. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord. 2000;15:873-878.
10. Metman LV, Del Dotto P, LePoole K, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol. 1999;56:1383-1386.
11. Snow BJ, Macdonald L, McAuley D, et al. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol. 2000;23:82-85.
12. Thomas A, Iacono D, Luciano AL, et al. Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75:141-143.
13. Verhagen Metman L, Del Dotto P, van den Munckhof P, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology. 1998;50:1323-1326.
14. Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology. 2004;62:381-388.
15. Bonifati V, Fabrizio E, Cipriani R, et al. Buspirone in levodopa-induced dyskinesias. Clin Neuropharmacol. 1994;17:73-82.
16. Goetz CG, Damier P, Hicking C, et al. Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trial. Mov Disord. 2007;22:179-186.
17. Deep Brain Stimulation for Parkinson’s Disease Study Group . Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med. 2001;345:956-963.
18. Visser-Vandewalle V, Van der Linden C, Temel Y, et al. Long-term motor effect of unilateral pallidal stimulation in 26 patients with advanced Parkinson disease. J Neurosurg. 2003;99:701-707.
19. Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord. 2006;21(Suppl 14):S290-S304.
November 19, 2008 — Dyskinesias, along with motor fluctuations, are the main motor complications of levodopa therapy. A retrospective analysis of studies investigating incidence of dyskinesias with levodopa treatment estimated that slightly more than one third of patients who had PD had dyskinesias after 4 to 6 years [1]. Early-onset PD and higher doses of levodopa are the biggest risk factors for the development of dyskinesias [2,3]. Dyskinesias may affect any part of the body and can be choreic or dystonic. They may manifest when plasma levodopa levels are at their peak (peak-dose dyskinesias), as plasma levodopa levels are rising and falling (diphasic dyskinesias), or when plasma levodopa levels are low (off-state dystonia). Dyskinesias typically are mild but may interfere with quality of life when painful or severe, as seen in advanced PD [4].
One way of treating dyskinesias is to modify the antiparkinsonian regimen. Peak-dose dyskinesias are related directly to the amount of levodopa given per dose, so decreasing individual doses generally reduces dyskinesias. The amount of clinical benefit to motor symptoms in PD may decline, however, and patients may experience increasing “off” periods. Thus, a decrease in individual doses of levodopa often has to be combined with more frequent administration, a practice termed dose fractionation. There are significant limitations to this approach, however, which are detailed in the article by Dewey elsewhere in this issue. Discontinuing catechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase (MAO)-B inhibitors also may be helpful in reducing peak-dose dyskinesias.
Sustained-release formulations in theory could reduce dyskinesias, as they are released slowly throughout the day. In practice, however, they tend to prolong the duration of dyskinesias and increase the severity of dyskinesias in the late afternoon or early evening [5]. Patients who have dyskinesias and are on sustained-release levodopa formulations may benefit from switching to immediate-release levodopa.
Diphasic dyskinesias can be difficult to treat. The same strategies can be tried, but there are no data to support one strategy over the other. Other options include overlapping the doses of levodopa to prevent trough plasma levodopa levels until late in the evening or administering very small doses of levodopa frequently (such as 50 mg of levodopa given hourly while awake) [6].
Strategies for treating off-state dystonias are similar to strategies to reduce motor fluctuations in PD and may include changing the levodopa dosing schedule or adding dopamine agonists, COMT inhibitors, or MAO-B inhibitors.
Recent evidence-based reviews recommend amantadine for treating dyskinesias in PD [7,8]. Amantadine is believed to have an antidyskinetic effect through its action at the N-methyl-D-aspartate receptor. Amantadine can reduce dyskinesias between 24% and 60% [9,10,11,12,13]. In one study, the effect of amantadine was maintained for up to a year. Some patients, however, are reported to have had rebound dyskinesias when amantadine was discontinued [12]. Side effects include confusion, peripheral edema, and livedo reticularis.
A double-blind, placebo-controlled trial of clozapine demonstrates an increase in “on” time without dyskinesias with a corresponding decrease in “on” time with dyskinesias [14]. The potential for agranulocytosis and the frequent blood monitoring required make it an unattractive agent, however. Buspirone is reported effective in one small crossover trial of 10 patients [15], but only seven patients completed the trial, and there are no other large randomized studies. Clinical trials of other drugs reported to be helpful for treating dyskinesias were uncontrolled or failed to show efficacy in large double-blind trials [6,16].
Although pallidotomy commonly was used as a surgical intervention for dyskinesias with good results [8], most surgical centers have turned to deep brain stimulation (DBS) to treat patients who have motor fluctuations and dyskinesias. There are two main targets for DBS in patients who have PD: the globus pallidus interna (GPi) and the subthalamic nucleus (STN). Although DBS of the GPi reduces dyskinesias in open-label reports and blinded evaluations of patients on and off stimulation [17,18], a recent practice parameter determined that there was insufficient evidence to determine the efficacy of GPi DBS for dyskinesias [7]. Part of this lack of evidence is because most centers prefer to place electrodes in the STN DBS. In a meta-analysis of outcomes, STN DBS reduced dyskinesias in patients who had PD by an average of 69.1% [19]. This occurs along with a reduction in levodopa dosage, which is mainly responsible for the improvement in dyskinesias. Based on existing studies, STN DBS is considered possibly effective for reducing motor fluctuations, dyskinesias, and antiparkinsonian medications in PD [7]. Adverse effects from DBS surgery may include surgical complications, such as hemorrhage, stroke, infection of the device, seizures, delirium, and stimulation-related effects, such as dystonia, confusion, paresthesias, dysarthria, and diplopia, depending on the stimulation site.
References
1. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16:448-458.
2. Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol. 2006;5:355-363.
3. Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol. 1999;246:1127-1133.
4. Pechevis M, Clarke CE, Vieregge P, et al. Effects of dyskinesias in Parkinson’s disease on quality of life and health-related costs: a prospective European study. Eur J Neurol. 2005;12:956-963.
5. Fabbrini G, Brotchie JM, Grandas F, et al. Levodopa-induced dyskinesias. Mov Disord. 2007;22:1379-1389quiz 1523.
6. Muenter MD. Patterns of dystonia in response to L-Dopa therapy for Parkinson’s disease. Mayo Clin Proc. 1977;52:163-174.
7. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66:983-995.
8. Goetz CG, Poewe W, Rascol O, et al. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to 2004. Mov Disord. 2005;20:523-539.
9. Luginger E, Wenning GK, Bosch S, et al. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson’s disease. Mov Disord. 2000;15:873-878.
10. Metman LV, Del Dotto P, LePoole K, et al. Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study. Arch Neurol. 1999;56:1383-1386.
11. Snow BJ, Macdonald L, McAuley D, et al. The effect of amantadine on levodopa-induced dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled study. Clin Neuropharmacol. 2000;23:82-85.
12. Thomas A, Iacono D, Luciano AL, et al. Duration of amantadine benefit on dyskinesia of severe Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75:141-143.
13. Verhagen Metman L, Del Dotto P, van den Munckhof P, et al. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology. 1998;50:1323-1326.
14. Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology. 2004;62:381-388.
15. Bonifati V, Fabrizio E, Cipriani R, et al. Buspirone in levodopa-induced dyskinesias. Clin Neuropharmacol. 1994;17:73-82.
16. Goetz CG, Damier P, Hicking C, et al. Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind placebo-controlled trial. Mov Disord. 2007;22:179-186.
17. Deep Brain Stimulation for Parkinson’s Disease Study Group . Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med. 2001;345:956-963.
18. Visser-Vandewalle V, Van der Linden C, Temel Y, et al. Long-term motor effect of unilateral pallidal stimulation in 26 patients with advanced Parkinson disease. J Neurosurg. 2003;99:701-707.
19. Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord. 2006;21(Suppl 14):S290-S304.
Wednesday, November 19, 2008
Neuroprotective Compounds Appear to Work - at Least in Mice
by Lynn Shapiro, Writer
In animal trials, Dr. Santosh D'Mello of the University of Texas at Dallas has found an exciting new compound to halt the loss of neurons. He can't reveal how the compound works until he publishes a peer-reviewed paper on it in six to nine months.
Even as the Society for Experimental Biology and Medicine announced last week that Dr. D'Mello, professor of molecular and cell biology, had identified a class of compound called 3-substituted indolones that prevent neurogeneration in tissue and mouse cultures, Dr. M'Mello told DOTmed News that his lab has just identified an even more exciting class of compounds called benzoxazines, which appear to be very effective in protecting neurons.
He hopes to find a compound to halt the progression of Alzheimer's, Parkinson's and ALS. "We tested these on neurons in cultured tissue and they stop neurodegeneration and are non-toxic, even at high doses," Dr. D'Mello says. He adds, "We have started testing these compounds in mice and one of them is protective in mice that have Huntington's disease."
Dr. D'Mello says that in the lab, he tests compounds on strains of tissues and mice with Huntington's disease, rather than on the diseases he wants to treat. "Huntington's is a rare disease but simpler to get a handle on than Alzheimer's and Parkinson's disease, because it is purely genetic. The other diseases have a complex mixture of environmental and genetic influences that remain to be understood."
Dr. D'Mello says he can't provide details about the benzoxazines he has isolated until he publishes a paper on his findings. "We're sending the manuscript out for review. It will be six to nine months before it's published," he says.
What Dr. D'Mello can reveal is this: He thinks he has found a new and promising class of neuroprotective compounds. The university has filed a patent application for both the synthesis of these compounds as well as their use in the treatment of neurogenerative diseases. He adds that the university would like to license the compounds to a pharmaceutical or biotech company, which would finish animal testing and if successful, see the drug through clinical trials.
Dr. D'Mello is working with Dr. Ed Blehl, a chemistry professor at Southern Methodist University, who is helping to design the benzoxazine derivatives. The two universities are sharing the patents.
Human Beings: Not So Easy
Dr. D'Mello cautions that while he has been studying neurodegeneration in his lab for the last 15 years, he has seen a field littered with failed compounds that do amazing things in culture and animals, but don't work in people.
"Tissue culture and mice are easy to work with but far removed from patients," he says. He adds, "It's difficult to say which compound will ultimately work, ours or others. So far, the track record hasn't been good although I'm optimistic that effective compounds will be found for patients."
Fortunately, treatments are available to ameliorate symptoms, especially in the case of Parkinson's disease, which causes a tremor due to the loss of the neurotransmitter dopamine.
"The symptoms associated with Parkinson's disease can temporarily be stopped with a combination of L-Dope and COMT, or with MAO inhibitors, so that patients (notably including actor Michael J. Fox and Newsweek columnist Michael Kinsley) may do well on the medicine for a decade or more," Dr. D'Mello says.
"However, such drugs are not a cure. They don't slow down the loss of neurons, which cause the disease. The attractive feature of the new compounds is that they may be able to stop the root cause of the disease."
For Alzheimer's disease patients, Aricept and other drugs on the market improve learning and memory, but the gains are modest.
There is no cure for either condition or for other neurodegenerative diseases such as ALS or Huntington's disease. After a while, the progressive death of nerve cells results in a loss of brain function and eventually, the patient dies. "Our major thrust is to find out what happens in a neuron that's degenerating and then as a biologist, my interest is investigating what molecules and genes are responsible for degeneration and which are involved in preventing neuronal loss," he says.
"Once we understand the workings of neurons in greater detail, we can prevent them from dying, by designing drugs."
The Society for Experimental Biology and Medicine said in its press release heralding Dr. D'Mello's discovery of indolones that "because the population is aging and people are living longer, the identification of small-molecule inhibitors of neuronal death is of urgent and critical importance."
In animal trials, Dr. Santosh D'Mello of the University of Texas at Dallas has found an exciting new compound to halt the loss of neurons. He can't reveal how the compound works until he publishes a peer-reviewed paper on it in six to nine months.
Even as the Society for Experimental Biology and Medicine announced last week that Dr. D'Mello, professor of molecular and cell biology, had identified a class of compound called 3-substituted indolones that prevent neurogeneration in tissue and mouse cultures, Dr. M'Mello told DOTmed News that his lab has just identified an even more exciting class of compounds called benzoxazines, which appear to be very effective in protecting neurons.
He hopes to find a compound to halt the progression of Alzheimer's, Parkinson's and ALS. "We tested these on neurons in cultured tissue and they stop neurodegeneration and are non-toxic, even at high doses," Dr. D'Mello says. He adds, "We have started testing these compounds in mice and one of them is protective in mice that have Huntington's disease."
Dr. D'Mello says that in the lab, he tests compounds on strains of tissues and mice with Huntington's disease, rather than on the diseases he wants to treat. "Huntington's is a rare disease but simpler to get a handle on than Alzheimer's and Parkinson's disease, because it is purely genetic. The other diseases have a complex mixture of environmental and genetic influences that remain to be understood."
Dr. D'Mello says he can't provide details about the benzoxazines he has isolated until he publishes a paper on his findings. "We're sending the manuscript out for review. It will be six to nine months before it's published," he says.
What Dr. D'Mello can reveal is this: He thinks he has found a new and promising class of neuroprotective compounds. The university has filed a patent application for both the synthesis of these compounds as well as their use in the treatment of neurogenerative diseases. He adds that the university would like to license the compounds to a pharmaceutical or biotech company, which would finish animal testing and if successful, see the drug through clinical trials.
Dr. D'Mello is working with Dr. Ed Blehl, a chemistry professor at Southern Methodist University, who is helping to design the benzoxazine derivatives. The two universities are sharing the patents.
Human Beings: Not So Easy
Dr. D'Mello cautions that while he has been studying neurodegeneration in his lab for the last 15 years, he has seen a field littered with failed compounds that do amazing things in culture and animals, but don't work in people.
"Tissue culture and mice are easy to work with but far removed from patients," he says. He adds, "It's difficult to say which compound will ultimately work, ours or others. So far, the track record hasn't been good although I'm optimistic that effective compounds will be found for patients."
Fortunately, treatments are available to ameliorate symptoms, especially in the case of Parkinson's disease, which causes a tremor due to the loss of the neurotransmitter dopamine.
"The symptoms associated with Parkinson's disease can temporarily be stopped with a combination of L-Dope and COMT, or with MAO inhibitors, so that patients (notably including actor Michael J. Fox and Newsweek columnist Michael Kinsley) may do well on the medicine for a decade or more," Dr. D'Mello says.
"However, such drugs are not a cure. They don't slow down the loss of neurons, which cause the disease. The attractive feature of the new compounds is that they may be able to stop the root cause of the disease."
For Alzheimer's disease patients, Aricept and other drugs on the market improve learning and memory, but the gains are modest.
There is no cure for either condition or for other neurodegenerative diseases such as ALS or Huntington's disease. After a while, the progressive death of nerve cells results in a loss of brain function and eventually, the patient dies. "Our major thrust is to find out what happens in a neuron that's degenerating and then as a biologist, my interest is investigating what molecules and genes are responsible for degeneration and which are involved in preventing neuronal loss," he says.
"Once we understand the workings of neurons in greater detail, we can prevent them from dying, by designing drugs."
The Society for Experimental Biology and Medicine said in its press release heralding Dr. D'Mello's discovery of indolones that "because the population is aging and people are living longer, the identification of small-molecule inhibitors of neuronal death is of urgent and critical importance."
Sodium Oxybate for Excessive Daytime Sleepiness in Parkinson Disease
An Open-Label Polysomnographic Study
William G. Ondo, MD; Thomas Perkins, MD; Todd Swick, MD; Keith L. Hull Jr, MD; J. Ernesto Jimenez, MEd; Tippy S. Garris, RN; Daniel Pardi, MS
Arch Neurol. 2008;65(10):1337-1340.
Background Many patients with Parkinson disease (PD) have excessive daytime sleepiness and numerous nocturnal sleep abnormalities.
Objective To determine the safety and efficacy of the controlled drug sodium oxybate in a multicenter, open-label, polysomnographic study in subjects with PD and sleep disorders.
Design, Setting, and Patients Inclusion required an Epworth Sleepiness Scale (ESS) score greater than 10 and any subjective nocturnal sleep concern, usually insomnia. An acclimation and screening polysomnogram was performed to exclude subjects with sleep-disordered breathing. The following evening, subjects underwent another polysomnogram, followed by an evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) while practically defined off ("off") PD medications, ESS (primary efficacy point), Pittsburgh Sleep Quality Inventory, and Fatigue Severity Scale. Subjects then started sodium oxybate therapy, which was titrated from 3 to 9 g per night in split doses (at bedtime and 4 hours later) across 6 weeks, and returned for subjective sleep assessments. They then returned at 12 weeks after initiating therapy for a third polysomnogram, an off-medication UPDRS evaluation, and subjective sleep assessments. Data are expressed as mean (SD).
Results We enrolled 38 subjects. At screening, 8 had sleep apnea (n = 7) or depression (n = 1). Twenty-seven of 30 subjects completed the study. Three dropped out owing to dizziness (n = 3) and concurrent depression (n = 1). The mean dose of sodium oxybate was 7.8 (1.7) g per night. The ESS score improved from 15.6 (4.2) to 9.0 (5.0) (P < .001); the Pittsburgh Sleep Quality Inventory score, from 10.9 (4.0) to 6.6 (3.9) (P < .001); and the Fatigue Severity Scale score, from 42.9 (13.2) to 36.3 (14.3) (P < .001). Mean slow-wave sleep time increased from 41.3 (33.2) to 78.0 (61.2) minutes (P = .005). Changes in off-medication UPDRS scores were not significant, from 28.4 (10.3) to 26.2 (9.6).
Conclusion Nocturnally administered sodium oxybate improved excessive daytime sleepiness and fatigue in PD.
William G. Ondo, MD; Thomas Perkins, MD; Todd Swick, MD; Keith L. Hull Jr, MD; J. Ernesto Jimenez, MEd; Tippy S. Garris, RN; Daniel Pardi, MS
Arch Neurol. 2008;65(10):1337-1340.
Background Many patients with Parkinson disease (PD) have excessive daytime sleepiness and numerous nocturnal sleep abnormalities.
Objective To determine the safety and efficacy of the controlled drug sodium oxybate in a multicenter, open-label, polysomnographic study in subjects with PD and sleep disorders.
Design, Setting, and Patients Inclusion required an Epworth Sleepiness Scale (ESS) score greater than 10 and any subjective nocturnal sleep concern, usually insomnia. An acclimation and screening polysomnogram was performed to exclude subjects with sleep-disordered breathing. The following evening, subjects underwent another polysomnogram, followed by an evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) while practically defined off ("off") PD medications, ESS (primary efficacy point), Pittsburgh Sleep Quality Inventory, and Fatigue Severity Scale. Subjects then started sodium oxybate therapy, which was titrated from 3 to 9 g per night in split doses (at bedtime and 4 hours later) across 6 weeks, and returned for subjective sleep assessments. They then returned at 12 weeks after initiating therapy for a third polysomnogram, an off-medication UPDRS evaluation, and subjective sleep assessments. Data are expressed as mean (SD).
Results We enrolled 38 subjects. At screening, 8 had sleep apnea (n = 7) or depression (n = 1). Twenty-seven of 30 subjects completed the study. Three dropped out owing to dizziness (n = 3) and concurrent depression (n = 1). The mean dose of sodium oxybate was 7.8 (1.7) g per night. The ESS score improved from 15.6 (4.2) to 9.0 (5.0) (P < .001); the Pittsburgh Sleep Quality Inventory score, from 10.9 (4.0) to 6.6 (3.9) (P < .001); and the Fatigue Severity Scale score, from 42.9 (13.2) to 36.3 (14.3) (P < .001). Mean slow-wave sleep time increased from 41.3 (33.2) to 78.0 (61.2) minutes (P = .005). Changes in off-medication UPDRS scores were not significant, from 28.4 (10.3) to 26.2 (9.6).
Conclusion Nocturnally administered sodium oxybate improved excessive daytime sleepiness and fatigue in PD.
End of clinical trial disappoints Parkinson's sufferer, his family
BY Anne Kelly
Philip Walker, record staff
CAMBRIDGE
A Cambridge man who might have benefited from a novel therapy for Parkinson's disease is disappointed that clinical trials have been halted.
Kees Vreugdenhil had adult eye cells injected into his brain 16 months ago in hopes of relieving some of his symptoms and helping advance research into Parkinson's.
The 70-year-old's sister and cousin also have a neurological movement disorder.
Vreugdenhil was excited to learn in August from Boston University Medical Center, where he was enrolled in the multi-site study, that he had actually received the treatment.
Half the 71 participants in the Phase 2 double-blind randomized trial had the treatment called Spheramine injected into both sides of the brain. The rest underwent what the researchers called a sham surgery, in which no cells were implanted.
The study was for patients with moderate to severe Parkinson's.
Vreugdenhil was told by his Boston doctor in August that the project was under review because results weren't as positive as hoped.
But he was surprised to learn recently that the pharmaceutical giant Bayer Inc., which had been partnering with Titan Pharmaceuticals on the trial, halted development of Spheramine in July.
"The STEPS trial with Spheramine did not show any difference in the outcome between the (sham surgery) and the actively treated patient groups," Adrienne Jackson, director of communications at Bayer Inc.'s Toronto office, wrote in an e-mail to the Waterloo Region Record.
Full results of the trial will be published in late December.
Vreugdenhil will be reading with interest.
"I was pretty hopeful that some positive result might come from this study," he said in an interview. "That appears not to be the case."
Vreugdenhil was given the option of continuing to go to Boston for monitoring, which he's decided to do.
The eye cells used in Spheramine are retinal epithelial pigment cells, which appeared promising for symptom relief because they produce levodopa.
Levodopa is a precursor to dopamine, a neurotransmitter that controls movement. In the brain, levodopa is converted to dopamine, which in people with Parkinson's is depleted because the neurotransmitters die.
It was hoped Spheramine would produce significant reduction in symptoms of the disease, which include tremor, muscle rigidity and stiffness, poor balance and slowed movement.
A Phase 1 trial with six patients showed promising results, and earlier results from Phase 2 were hopeful.
Dr. Mandar Jog, director of the Movement Disorders Clinic at London Health Sciences Centre, said placing dopamine-producing cells in a part of the brain where dopamine is missing makes sense.
"The science behind it is solid," Jog said. But the treatment was controversial because it involved expensive, invasive surgery that had the potential to help only a small segment of people with Parkinson's, he said.
Its lack of success won't be fully understood until results are published and peer-reviewed, Jog said.
Vreugdenhil decided to enrol after his daughter saw a newspaper ad for the trial in December 2006.
The delicate four-hour surgery to implant the cells was done at Emory University Hospital in Atlanta. Vreugdenhil is about to make his 14th trip to Boston University Medical Centre, where he has undergone two days of tests on each trip.
All travel expenses for him and his wife, Liz, are covered and they expect to make several trips to Boston over the next year or so for monitoring.
Although he noticed no improvement, Vreugdenhil doesn't feel it was a wasted effort.
"I have no regrets and would do it again if I had the opportunity," said the retired Union Gas executive, who was diagnosed in 1999. He is eager to advance scientific research into a disease he hopes will never afflict his children or grandchildren.
"I was willing to do anything to prevent them from getting it,'' he said. "It is my contribution to science. If there was something in it for me that would be wonderful."
While the goal of the eye cell therapy was symptom relief, not prevention, every Parkinson's experiment advances scientists' understanding of the degenerative disease.
"You always gain some knowledge and information," Liz said.
Vreugdenhil's symptoms began at age 55, with deteriorating handwriting and a weakening singing voice.
When his family doctor noticed a change in his facial expression in 1999, he suspected Parkinson's and had him tested.
Today Vreugdenhil experiences weakness, balance problems and a shuffling gait, which requires him to use a cane or walker. His face has a masklike appearance, typical of some people with Parkinson's.
He takes 17 pills a day.
"It's quite a fistful. I look at it every morning and say 'this can't be good for me.' "
Vreugdenhil previously participated in a study at Wilfrid Laurier's Movement Disorders Research and Rehabilitation Centre.
Between trips to Boston, he and Liz carry on with a busy life. The couple founded a Parkinson's support group after moving from Chatham two years ago to be near their daughter and raise funds for the Parkinson Society.
Philip Walker, record staff
CAMBRIDGE
A Cambridge man who might have benefited from a novel therapy for Parkinson's disease is disappointed that clinical trials have been halted.
Kees Vreugdenhil had adult eye cells injected into his brain 16 months ago in hopes of relieving some of his symptoms and helping advance research into Parkinson's.
The 70-year-old's sister and cousin also have a neurological movement disorder.
Vreugdenhil was excited to learn in August from Boston University Medical Center, where he was enrolled in the multi-site study, that he had actually received the treatment.
Half the 71 participants in the Phase 2 double-blind randomized trial had the treatment called Spheramine injected into both sides of the brain. The rest underwent what the researchers called a sham surgery, in which no cells were implanted.
The study was for patients with moderate to severe Parkinson's.
Vreugdenhil was told by his Boston doctor in August that the project was under review because results weren't as positive as hoped.
But he was surprised to learn recently that the pharmaceutical giant Bayer Inc., which had been partnering with Titan Pharmaceuticals on the trial, halted development of Spheramine in July.
"The STEPS trial with Spheramine did not show any difference in the outcome between the (sham surgery) and the actively treated patient groups," Adrienne Jackson, director of communications at Bayer Inc.'s Toronto office, wrote in an e-mail to the Waterloo Region Record.
Full results of the trial will be published in late December.
Vreugdenhil will be reading with interest.
"I was pretty hopeful that some positive result might come from this study," he said in an interview. "That appears not to be the case."
Vreugdenhil was given the option of continuing to go to Boston for monitoring, which he's decided to do.
The eye cells used in Spheramine are retinal epithelial pigment cells, which appeared promising for symptom relief because they produce levodopa.
Levodopa is a precursor to dopamine, a neurotransmitter that controls movement. In the brain, levodopa is converted to dopamine, which in people with Parkinson's is depleted because the neurotransmitters die.
It was hoped Spheramine would produce significant reduction in symptoms of the disease, which include tremor, muscle rigidity and stiffness, poor balance and slowed movement.
A Phase 1 trial with six patients showed promising results, and earlier results from Phase 2 were hopeful.
Dr. Mandar Jog, director of the Movement Disorders Clinic at London Health Sciences Centre, said placing dopamine-producing cells in a part of the brain where dopamine is missing makes sense.
"The science behind it is solid," Jog said. But the treatment was controversial because it involved expensive, invasive surgery that had the potential to help only a small segment of people with Parkinson's, he said.
Its lack of success won't be fully understood until results are published and peer-reviewed, Jog said.
Vreugdenhil decided to enrol after his daughter saw a newspaper ad for the trial in December 2006.
The delicate four-hour surgery to implant the cells was done at Emory University Hospital in Atlanta. Vreugdenhil is about to make his 14th trip to Boston University Medical Centre, where he has undergone two days of tests on each trip.
All travel expenses for him and his wife, Liz, are covered and they expect to make several trips to Boston over the next year or so for monitoring.
Although he noticed no improvement, Vreugdenhil doesn't feel it was a wasted effort.
"I have no regrets and would do it again if I had the opportunity," said the retired Union Gas executive, who was diagnosed in 1999. He is eager to advance scientific research into a disease he hopes will never afflict his children or grandchildren.
"I was willing to do anything to prevent them from getting it,'' he said. "It is my contribution to science. If there was something in it for me that would be wonderful."
While the goal of the eye cell therapy was symptom relief, not prevention, every Parkinson's experiment advances scientists' understanding of the degenerative disease.
"You always gain some knowledge and information," Liz said.
Vreugdenhil's symptoms began at age 55, with deteriorating handwriting and a weakening singing voice.
When his family doctor noticed a change in his facial expression in 1999, he suspected Parkinson's and had him tested.
Today Vreugdenhil experiences weakness, balance problems and a shuffling gait, which requires him to use a cane or walker. His face has a masklike appearance, typical of some people with Parkinson's.
He takes 17 pills a day.
"It's quite a fistful. I look at it every morning and say 'this can't be good for me.' "
Vreugdenhil previously participated in a study at Wilfrid Laurier's Movement Disorders Research and Rehabilitation Centre.
Between trips to Boston, he and Liz carry on with a busy life. The couple founded a Parkinson's support group after moving from Chatham two years ago to be near their daughter and raise funds for the Parkinson Society.
13th October 2008 - New clinical trial
The Michael J. Fox Foundation is to carry out a clinical trial using the Nexalin Device. For more information go to The Michael J.Fox Foundation. Nexalin Therapy is a technology that uses a mild stimulation of the brain to treat a variety of mood disorders, specifically Anxiety, Depression, and Insomnia. The waveform of Nexalin is administered by placing medical grade conductive pads produced specifically for the Nexalin device on the forehead and behind each ear, which are connected to the Nexalin device with thin cables. The patient is placed in a reclining chair for the duration of a treatment session, which typically lasts for approximately forty minutes. For more information go to Nexalin Advanced Therapy. The disorders usually treated share a similar biochemistry with Parkinson's Disease. The intended effect appears to be like a milder version of DBS (Deep Brain Stimulation) but without using surgery as DBS does. In January 2008, a number of Parkinson's Disease patients carried out their own informal study. For more information go to ParkinsonsRebels.
Future PD Therapy: Potential Role for Nicotine
New research suggests that nicotine or nicotine agonists may play an important role in the future of Parkinson's disease therapy.
Dopaminergic neurons of the striatum also bear so-called nicotinic acetylcholine receptors (nAchRs). Each nAchR is composed of five subunits, drawn from multiple possible types of alpha and beta subunits. Recent work by Drenan et al. demonstrate that one such subunit, alpha-6, appears to play a special role in the striatum.
--They showed in mice that specific stimulation of the alpha-6 subunit prompted dopamine release from striatal dopamine neurons, indicating the importance of nAchRs containing alpha-6 as modulators of dopaminergic signaling.
--Results of stimulation suggested that alpha-6 containing nAchRs do not occur on striatal GABA neurons, even though nAchRs of other subunit concentration do. This finding suggests that alpha-6-specific stimulation may be able to avoid off-target effects of less specific nicotinic receptor agonists.
--Repeated stimulation did not induce tolerance or sensitization, suggesting drugs targeting alpha-6 might have less potential for abuse, and "might avoid well known use-dependent side effects [of direct dopamine stimulation] such as dyskinesias," the authors say.
In vivo activation of midbrain dopamine neurons via sensitive, high-affinity alpha-6* nicotinic acetylcholine receptors. RM Drenan, SR Grady, P Whiteaker, et al.Neuron, 2008;60:123-136
The potential of nicotinic stimulation for PD therapy was also recently highlighted in a review by Quik et al. They outline the case for nicotine stimulation as follows:
--Nicotinic receptors are found presynaptically on nigrostriatal dopaminergic neurons, as well as on GABAergic and cholinergic neurons in the striatum, and nicotinic stimulation affects motor function in animals with nigrostriatal damage.
--alpha-6-containing dopaminergic neurons are more susceptible to damage in PD than neurons with other subtypes predominating. These receptors, therefore, "may represent promising pharmacologic targets for Parkinson's disease for neuroprotection and/or symptomatic improvement.
--Epidemiologic studies consistently show that smokers have a lower risk of developing PD. The effect is dose-dependent and wanes after smoking cessation, "consistent with a true biologic protective effect of tobacco use."
--Nicotine stimulation is neuroprotective in animal models of PD and cell culture systems.
--Nicotinic stimulation improves motor symptoms in animal models. Variable outcomes have been reported in humans from case studies and small trials.
--Nicotine reduces dyskinesias in animal models.
"These combined data indicate that nicotine or nicotinic agonists may be useful for Parkinson's disease therapy," potentially including neuroprotection, symptomatic improvement, and alleviation or prevention of dyskinesias, the authors conclude.
Nicotine and Parkinson's disease: Implications for therapy. M Quik, K O'Leary, CM Tanner. Movement Disorders 2008;23:1641-1652
Dopaminergic neurons of the striatum also bear so-called nicotinic acetylcholine receptors (nAchRs). Each nAchR is composed of five subunits, drawn from multiple possible types of alpha and beta subunits. Recent work by Drenan et al. demonstrate that one such subunit, alpha-6, appears to play a special role in the striatum.
--They showed in mice that specific stimulation of the alpha-6 subunit prompted dopamine release from striatal dopamine neurons, indicating the importance of nAchRs containing alpha-6 as modulators of dopaminergic signaling.
--Results of stimulation suggested that alpha-6 containing nAchRs do not occur on striatal GABA neurons, even though nAchRs of other subunit concentration do. This finding suggests that alpha-6-specific stimulation may be able to avoid off-target effects of less specific nicotinic receptor agonists.
--Repeated stimulation did not induce tolerance or sensitization, suggesting drugs targeting alpha-6 might have less potential for abuse, and "might avoid well known use-dependent side effects [of direct dopamine stimulation] such as dyskinesias," the authors say.
In vivo activation of midbrain dopamine neurons via sensitive, high-affinity alpha-6* nicotinic acetylcholine receptors. RM Drenan, SR Grady, P Whiteaker, et al.Neuron, 2008;60:123-136
The potential of nicotinic stimulation for PD therapy was also recently highlighted in a review by Quik et al. They outline the case for nicotine stimulation as follows:
--Nicotinic receptors are found presynaptically on nigrostriatal dopaminergic neurons, as well as on GABAergic and cholinergic neurons in the striatum, and nicotinic stimulation affects motor function in animals with nigrostriatal damage.
--alpha-6-containing dopaminergic neurons are more susceptible to damage in PD than neurons with other subtypes predominating. These receptors, therefore, "may represent promising pharmacologic targets for Parkinson's disease for neuroprotection and/or symptomatic improvement.
--Epidemiologic studies consistently show that smokers have a lower risk of developing PD. The effect is dose-dependent and wanes after smoking cessation, "consistent with a true biologic protective effect of tobacco use."
--Nicotine stimulation is neuroprotective in animal models of PD and cell culture systems.
--Nicotinic stimulation improves motor symptoms in animal models. Variable outcomes have been reported in humans from case studies and small trials.
--Nicotine reduces dyskinesias in animal models.
"These combined data indicate that nicotine or nicotinic agonists may be useful for Parkinson's disease therapy," potentially including neuroprotection, symptomatic improvement, and alleviation or prevention of dyskinesias, the authors conclude.
Nicotine and Parkinson's disease: Implications for therapy. M Quik, K O'Leary, CM Tanner. Movement Disorders 2008;23:1641-1652
Treatment of tremor with histamine h3 inverse agonists or histamine h3 antagonists
Agent: Merck And Co., Inc - Rahway, NJ, US
Inventors: Michael J. Marino, Guy R. Seabrook
USPTO Applicaton #: 20080242657 - Class: 51421113 (USPTO)
The Patent Description & Claims data below is from USPTO Patent Application 20080242657.
Brief Patent Description
BACKGROUND OF THE INVENTION
Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone. The akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022).
Essential tremor is a disorder that affects 5-10 million persons in the United States. It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts. Essential tremor is a progressive neurologic disorder and can cause substantial disability in some patients. Although there currently is no cure for essential tremor, pharmacologic and surgical treatments can provide some benefit. The clinical diagnosis of essential tremor is reviewed by Pahwa et al., Am. J. Medicine, 115, 134-142 (Aug. 1, 2003), and current treatments for essential tremor are reviewed by Lyons et al., Drug Safety, 26(7): 461-481 (2003).
Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists. Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain. Levodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances.
Tremor, chorea, myoclonus, tics and dystonias, are treated with a variety of pharmacological agents. Thus, for example, tremor may be treated with benzodiazepines such as diazepam; chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine; tics may be controlled with neuroleptics such as haloperidol or pimozide; and dystonias tend to be treated with levodopa, benzodiazepines such as diazepam, anticholinergics such as benzhexyl, phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine.
Treatment of psychotic disorders with neuroleptic agents, such as haloperidol may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. PCT Patent Publication WO 01/30346 discloses the use of histamine H3 agonists for the treatment of dyskinesia.
There exists a patient population in whom tremor is inadequately treated with existing neuroleptic therapy. Furthermore, some patients may be adversely affected by the side-effects of neuroleptic drugs. In view of the shortcomings of existing therapy, there is a need for new, safe and effective treatment for tremor and movement disorders.
SUMMARY OF THE INVENTION
The present invention is directed to the use of a histamine H3 inverse agonist or antagonist, alone or in combination with a neuroleptic agent, for treating or preventing movement disorders, including tremor, such as essential tremor, and tremor associated with Parkinson's disease, cranofacial trauma, multiple sclerosis, stroke, dystonia, neuropathic induced tremor, toxic induced tremor, or drug induced tremor.
DESCRIPTION OF THE INVENTION
The present invention is directed to the use of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof, alone or in combination with a neuroleptic agent, for treating or preventing movement disorders, including tremor, such as essential tremor, and tremor associated with Parkinson's disease, cranofacial trauma, multiple sclerosis, stroke, dystonia, neuropathic induced tremor, toxic induced tremor, drug induced tremor, or tremor associated with dyskinesia, tardive diskinesia, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonian-ALS dementia complex, basal ganglia calcification, akinesia, akinetic-rigid syndrome, bradykinesia, dystonia, medication-induced parkinsonian, Gilles de la Tourette syndrome, Huntingon disease, chorea, myoclonus, and tick disorder.
An embodiment of the present invention is directed to a method for treating, controlling, ameliorating or reducing the risk of a movement disorder in a patient in need thereof that comprises administering to the patient a therapeutically effective amount of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof.
Although a histamine H3 inverse agonist or antagonist is useful alone for movement disorders, it will be appreciated that a combination of a conventional antiparkinsonian drug with a histamine H3 inverse agonist or antagonist may provide an enhanced effect in the treatment of tremor or akinetic-rigid disorders such as parkinsonism. Such a combination may enable a lower dose of the antiparkinsonian agent to be used without compromising the efficacy of the antiparkinsonian agent, thereby minimizing the risk of adverse side-effects.
It will be further appreciated that a combination of a conventional neuroleptic drug with a histamine H3 inverse agonist or antagonist or a pharmaceutically acceptable salt thereof may provide an enhanced effect in the treatment of dyskinesias. Such a combination may enable a lower dose of the neuroleptic agent to be used without compromising the efficacy of the neuroleptic agent, thereby minimising the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of a histamine H3 inverse agonist or antagonist, adverse side-effects caused by the neuroleptic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
The present invention also provides a method for the treatment or prevention of dyskinesias, which method comprises administration to a patient in need of such treatment of an amount of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof and an amount of a neuroleptic agent, such that together they give effective relief.
Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone. The akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022).
Essential tremor is a disorder that affects 5-10 million persons in the United States. It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts. Essential tremor is a progressive neurologic disorder and can cause substantial disability in some patients. Although there currently is no cure for essential tremor, pharmacologic and surgical treatments can provide some benefit. The clinical diagnosis of essential tremor is reviewed by Pahwa et al., Am. J. Medicine, 115, 134-142 (Aug. 1, 2003), and current treatments for essential tremor are reviewed by Lyons et al., Drug Safety, 26(7): 461-481 (2003).
Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists. Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain. Levodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances.
Tremor, chorea, myoclonus, tics and dystonias, are treated with a variety of pharmacological agents. Thus, for example, tremor may be treated with benzodiazepines such as diazepam; chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine; tics may be controlled with neuroleptics such as haloperidol or pimozide; and dystonias tend to be treated with levodopa, benzodiazepines such as diazepam, anticholinergics such as benzhexyl, phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine.
Treatment of psychotic disorders with neuroleptic agents, such as haloperidol may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. PCT Patent Publication WO 01/30346 discloses the use of histamine H3 agonists for the treatment of dyskinesia.
There exists a patient population in whom tremor is inadequately treated with existing neuroleptic therapy. Furthermore, some patients may be adversely affected by the side-effects of neuroleptic drugs. In view of the shortcomings of existing therapy, there is a need for new, safe and effective treatment for tremor and movement disorders.
Inventors: Michael J. Marino, Guy R. Seabrook
USPTO Applicaton #: 20080242657 - Class: 51421113 (USPTO)
The Patent Description & Claims data below is from USPTO Patent Application 20080242657.
Brief Patent Description
BACKGROUND OF THE INVENTION
Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone. The akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022).
Essential tremor is a disorder that affects 5-10 million persons in the United States. It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts. Essential tremor is a progressive neurologic disorder and can cause substantial disability in some patients. Although there currently is no cure for essential tremor, pharmacologic and surgical treatments can provide some benefit. The clinical diagnosis of essential tremor is reviewed by Pahwa et al., Am. J. Medicine, 115, 134-142 (Aug. 1, 2003), and current treatments for essential tremor are reviewed by Lyons et al., Drug Safety, 26(7): 461-481 (2003).
Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists. Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain. Levodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances.
Tremor, chorea, myoclonus, tics and dystonias, are treated with a variety of pharmacological agents. Thus, for example, tremor may be treated with benzodiazepines such as diazepam; chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine; tics may be controlled with neuroleptics such as haloperidol or pimozide; and dystonias tend to be treated with levodopa, benzodiazepines such as diazepam, anticholinergics such as benzhexyl, phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine.
Treatment of psychotic disorders with neuroleptic agents, such as haloperidol may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. PCT Patent Publication WO 01/30346 discloses the use of histamine H3 agonists for the treatment of dyskinesia.
There exists a patient population in whom tremor is inadequately treated with existing neuroleptic therapy. Furthermore, some patients may be adversely affected by the side-effects of neuroleptic drugs. In view of the shortcomings of existing therapy, there is a need for new, safe and effective treatment for tremor and movement disorders.
SUMMARY OF THE INVENTION
The present invention is directed to the use of a histamine H3 inverse agonist or antagonist, alone or in combination with a neuroleptic agent, for treating or preventing movement disorders, including tremor, such as essential tremor, and tremor associated with Parkinson's disease, cranofacial trauma, multiple sclerosis, stroke, dystonia, neuropathic induced tremor, toxic induced tremor, or drug induced tremor.
DESCRIPTION OF THE INVENTION
The present invention is directed to the use of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof, alone or in combination with a neuroleptic agent, for treating or preventing movement disorders, including tremor, such as essential tremor, and tremor associated with Parkinson's disease, cranofacial trauma, multiple sclerosis, stroke, dystonia, neuropathic induced tremor, toxic induced tremor, drug induced tremor, or tremor associated with dyskinesia, tardive diskinesia, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonian-ALS dementia complex, basal ganglia calcification, akinesia, akinetic-rigid syndrome, bradykinesia, dystonia, medication-induced parkinsonian, Gilles de la Tourette syndrome, Huntingon disease, chorea, myoclonus, and tick disorder.
An embodiment of the present invention is directed to a method for treating, controlling, ameliorating or reducing the risk of a movement disorder in a patient in need thereof that comprises administering to the patient a therapeutically effective amount of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof.
Although a histamine H3 inverse agonist or antagonist is useful alone for movement disorders, it will be appreciated that a combination of a conventional antiparkinsonian drug with a histamine H3 inverse agonist or antagonist may provide an enhanced effect in the treatment of tremor or akinetic-rigid disorders such as parkinsonism. Such a combination may enable a lower dose of the antiparkinsonian agent to be used without compromising the efficacy of the antiparkinsonian agent, thereby minimizing the risk of adverse side-effects.
It will be further appreciated that a combination of a conventional neuroleptic drug with a histamine H3 inverse agonist or antagonist or a pharmaceutically acceptable salt thereof may provide an enhanced effect in the treatment of dyskinesias. Such a combination may enable a lower dose of the neuroleptic agent to be used without compromising the efficacy of the neuroleptic agent, thereby minimising the risk of adverse side-effects. A yet further advantage of such a combination is that, due to the action of a histamine H3 inverse agonist or antagonist, adverse side-effects caused by the neuroleptic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
The present invention also provides a method for the treatment or prevention of dyskinesias, which method comprises administration to a patient in need of such treatment of an amount of a histamine H3 inverse agonist or histamine H3 antagonist, or a pharmaceutically acceptable salt thereof and an amount of a neuroleptic agent, such that together they give effective relief.
Diseases of the extrapyramidal motor systems cause either a loss of movement (akinesia) accompanied by an increase in muscle tone (rigidity) or abnormal involuntary movements (dyskinesias) often accompanied by a reduction in muscle tone. The akinetic-rigid syndrome called parkinsonism, and the dyskinesias represent opposite ends of the spectrum of movement disorders (for review see C. D. Marsden in Oxford Textbook of Medicine, 3rd Edition, Oxford University Press, 1996, vol. 3, pages 3998-4022).
Essential tremor is a disorder that affects 5-10 million persons in the United States. It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts. Essential tremor is a progressive neurologic disorder and can cause substantial disability in some patients. Although there currently is no cure for essential tremor, pharmacologic and surgical treatments can provide some benefit. The clinical diagnosis of essential tremor is reviewed by Pahwa et al., Am. J. Medicine, 115, 134-142 (Aug. 1, 2003), and current treatments for essential tremor are reviewed by Lyons et al., Drug Safety, 26(7): 461-481 (2003).
Treatment of akinetic-rigid conditions such as parkinsonism typically involves the use of levodopa, anticholinergics or dopamine agonists. Levodopa is converted into dopamine in the brain by the enzyme dopa decarboxylase. However, this enzyme is also present in the gut wall, liver, kidney and cerebral capillaries, thus the peripheral formation of levodopa metabolites may give rise to side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. This peripheral decarboxylation is largely prevented by the addition of a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which themselves do not penetrate the brain. Levodopa combined with carbidopa (SINEMET™) or benserazide (MADOPAR™) is now the treatment of choice when levodopa is indicated. Even then, this combination therapy may be associated with side-effects such as dyskinesias and psychiatric disturbances.
Tremor, chorea, myoclonus, tics and dystonias, are treated with a variety of pharmacological agents. Thus, for example, tremor may be treated with benzodiazepines such as diazepam; chorea may be treated with diazepam, a phenothiazide or haloperidol, or tetrabenazine; tics may be controlled with neuroleptics such as haloperidol or pimozide; and dystonias tend to be treated with levodopa, benzodiazepines such as diazepam, anticholinergics such as benzhexyl, phenothiazines and other neuroleptics such as haloperidol, and tetrabenazine.
Treatment of psychotic disorders with neuroleptic agents, such as haloperidol may be at the expense of a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function. PCT Patent Publication WO 01/30346 discloses the use of histamine H3 agonists for the treatment of dyskinesia.
There exists a patient population in whom tremor is inadequately treated with existing neuroleptic therapy. Furthermore, some patients may be adversely affected by the side-effects of neuroleptic drugs. In view of the shortcomings of existing therapy, there is a need for new, safe and effective treatment for tremor and movement disorders.
Rasagiline Slows Functional Decline in Patients With Parkinson's: Presented at ANA
By Andrew N. Wilner, MD
SALT LAKE CITY, Utah -- September 24, 2008 -- Early treatment with rasagiline 1 mg slows functional decline in patients with Parkinson's disease, according to research presented here at the American Neurological Association (ANA) 133rd Annual Meeting.
The ADAGIO delayed-start trial was the first prospectively-designed clinical trial to test the potential of rasagiline to delay the progression of Parkinson's disease.
Rasagiline is a selective, irreversible, second-generation monoamine oxidase B inhibitor and may possess neuroprotective properties, possibly due to its propargyl moiety, said Warren Olanow, MD, Mount Sinai School of Medicine, New York, New York.
"Neuroprotection is the holy grail of treatment for Parkinson's disease," Dr. Olanow observed in a presentation on September 23. "Symptoms such as falling, freezing, and dementia are nondopaminergic and a major cause of disability in the later stages of Parkinson's disease. We need neuroprotective therapies to address these symptoms."
For their study, Dr. Olanow and colleagues enrolled 1,176 patients with early, previously untreated Parkinson's disease. Diagnosis was based on the presence of resting tremor, bradykinesia, or rigidity. The study used a delayed-start design with 4 treatment arms: rasagiline 1 or 2 mg/day for 72 weeks (early start) or placebo for 36 weeks followed by rasagiline 1 or 2 mg/day for 36 weeks (delayed start).
At the end of the first, double-blind, placebo-controlled, 36-week phase, if there were a difference in outcome as measured by the Total Unified Parkinson's Disease Rating Scale (UPDRS), the placebo group would be switched to rasagiline.
Results at the end of 36 weeks show a significant benefit with rasagiline 1 mg compared with placebo in the UPDRS score as measured by the slope of rasagiline minus the slope of placebo = -0.05 (P = .0133). At that time, the placebo patients were switched to rasagiline 1 mg and both groups were followed for another 36 weeks.
At the end of 72 weeks, the early rasagiline group maintained its superiority. Further, there was noninferiority of the slopes of the 2 active-treatment groups, which suggests that the group that began treatment late could not catch up to the benefits achieved in UPDRS by the early treated group.
With rasagiline 2 mg, there was significant benefit at the end of 36 weeks compared to placebo. However, at the end of an additional 36 weeks, both groups had similar efficacy, suggesting there was no advantage of starting rasagiline 2 mg early. Dr. Olanow acknowledged that there was not a ready explanation why the 1 mg dose but not the 2 mg dose demonstrated persistent superiority to the late- start treatment.
Dr. Olanow concluded, "Early treatment with rasagiline 1 mg provides a benefit that cannot be achieved with later introduction of the same drug. This may be evidence of neuroprotection or preservation or enhancement of supportive, compensatory mechanisms."
SALT LAKE CITY, Utah -- September 24, 2008 -- Early treatment with rasagiline 1 mg slows functional decline in patients with Parkinson's disease, according to research presented here at the American Neurological Association (ANA) 133rd Annual Meeting.
The ADAGIO delayed-start trial was the first prospectively-designed clinical trial to test the potential of rasagiline to delay the progression of Parkinson's disease.
Rasagiline is a selective, irreversible, second-generation monoamine oxidase B inhibitor and may possess neuroprotective properties, possibly due to its propargyl moiety, said Warren Olanow, MD, Mount Sinai School of Medicine, New York, New York.
"Neuroprotection is the holy grail of treatment for Parkinson's disease," Dr. Olanow observed in a presentation on September 23. "Symptoms such as falling, freezing, and dementia are nondopaminergic and a major cause of disability in the later stages of Parkinson's disease. We need neuroprotective therapies to address these symptoms."
For their study, Dr. Olanow and colleagues enrolled 1,176 patients with early, previously untreated Parkinson's disease. Diagnosis was based on the presence of resting tremor, bradykinesia, or rigidity. The study used a delayed-start design with 4 treatment arms: rasagiline 1 or 2 mg/day for 72 weeks (early start) or placebo for 36 weeks followed by rasagiline 1 or 2 mg/day for 36 weeks (delayed start).
At the end of the first, double-blind, placebo-controlled, 36-week phase, if there were a difference in outcome as measured by the Total Unified Parkinson's Disease Rating Scale (UPDRS), the placebo group would be switched to rasagiline.
Results at the end of 36 weeks show a significant benefit with rasagiline 1 mg compared with placebo in the UPDRS score as measured by the slope of rasagiline minus the slope of placebo = -0.05 (P = .0133). At that time, the placebo patients were switched to rasagiline 1 mg and both groups were followed for another 36 weeks.
At the end of 72 weeks, the early rasagiline group maintained its superiority. Further, there was noninferiority of the slopes of the 2 active-treatment groups, which suggests that the group that began treatment late could not catch up to the benefits achieved in UPDRS by the early treated group.
With rasagiline 2 mg, there was significant benefit at the end of 36 weeks compared to placebo. However, at the end of an additional 36 weeks, both groups had similar efficacy, suggesting there was no advantage of starting rasagiline 2 mg early. Dr. Olanow acknowledged that there was not a ready explanation why the 1 mg dose but not the 2 mg dose demonstrated persistent superiority to the late- start treatment.
Dr. Olanow concluded, "Early treatment with rasagiline 1 mg provides a benefit that cannot be achieved with later introduction of the same drug. This may be evidence of neuroprotection or preservation or enhancement of supportive, compensatory mechanisms."
Surgery Provides Better Quality of Life Than Medical Therapy for Advanced Parkinson's Disease: Presented at ANA
By Andrew N. Wilner, MD
SALT LAKE CITY, Utah -- September 25, 2008 -- Surgical treatment of advanced Parkinson's disease (PD) improves quality of life compared to medical treatment, according to research presented here at the American Neurological Association (ANA) 133rd Annual Meeting.
Dubbed "PD SURG," the large, randomised assessment of the relative cost-effectiveness of surgery for PD, is being conducted by researchers in the United Kingdom.
The study enrolled 366 patients with advanced disease who were randomised to surgical (n = 183) or medical treatment (n = 183). Dyskinesia (73%) and severe "off" periods (77%) were the main indications for surgery.
Study patients were a mean of 59 years old, 71% were men, and mean duration of disease was 11 years, according to a works-in-progress presentation held here on September 23. All subjects rated stage <2.5 in the "on" state using the Hoehn and Yahr scale (0 to 5 scale indicating the relative level of disability from PD symptoms).
Deep brain stimulation (DBS) of the subthalamic nucleus was the selected surgical procedure for 98% of the patients in the surgical arm, noted lead author Adrian Williams, MD, Queen Elizabeth Medical Centre, Birmingham, United Kingdom.
At 1-year follow up, patients who had undergone surgery demonstrated statistically significant improvements in 3 of the 8 domains of the Parkinson's Disease Questionnaire (PDQ-39) -- mobility, activities of daily living, and bodily discomfort -- compared with those who had followed medical therapy.
Improvements were also seen in emotional well-being, stigma, and cognition. The overall PDQ score improved by 5.4 points in the surgery arm, but decreased by 0.3 in the medical-therapy arm (P = .0003).
In addition, 15% of the surgery patients had improvements of 16 or more points on the PDQ-39 compared with 2% of the medical-therapy patients. Surgery patients who had major improvements on the PDQ-39 tended to be younger (P = .009), have a shorter duration of PD (P = .05), and have worse PDQ-39 baseline scores (P < .0001).
On the Unified Parkinson's Disease Rating Scale, statistically significant improvements occurred in the surgery group compared with the medical-therapy group.
The authors concluded that the quality-of-life improvements seen after surgery in this study are likely to be meaningful to patients with advanced PD.
PD SURG is the largest study to date comparing surgical to medical treatment in patients with PD.
SALT LAKE CITY, Utah -- September 25, 2008 -- Surgical treatment of advanced Parkinson's disease (PD) improves quality of life compared to medical treatment, according to research presented here at the American Neurological Association (ANA) 133rd Annual Meeting.
Dubbed "PD SURG," the large, randomised assessment of the relative cost-effectiveness of surgery for PD, is being conducted by researchers in the United Kingdom.
The study enrolled 366 patients with advanced disease who were randomised to surgical (n = 183) or medical treatment (n = 183). Dyskinesia (73%) and severe "off" periods (77%) were the main indications for surgery.
Study patients were a mean of 59 years old, 71% were men, and mean duration of disease was 11 years, according to a works-in-progress presentation held here on September 23. All subjects rated stage <2.5 in the "on" state using the Hoehn and Yahr scale (0 to 5 scale indicating the relative level of disability from PD symptoms).
Deep brain stimulation (DBS) of the subthalamic nucleus was the selected surgical procedure for 98% of the patients in the surgical arm, noted lead author Adrian Williams, MD, Queen Elizabeth Medical Centre, Birmingham, United Kingdom.
At 1-year follow up, patients who had undergone surgery demonstrated statistically significant improvements in 3 of the 8 domains of the Parkinson's Disease Questionnaire (PDQ-39) -- mobility, activities of daily living, and bodily discomfort -- compared with those who had followed medical therapy.
Improvements were also seen in emotional well-being, stigma, and cognition. The overall PDQ score improved by 5.4 points in the surgery arm, but decreased by 0.3 in the medical-therapy arm (P = .0003).
In addition, 15% of the surgery patients had improvements of 16 or more points on the PDQ-39 compared with 2% of the medical-therapy patients. Surgery patients who had major improvements on the PDQ-39 tended to be younger (P = .009), have a shorter duration of PD (P = .05), and have worse PDQ-39 baseline scores (P < .0001).
On the Unified Parkinson's Disease Rating Scale, statistically significant improvements occurred in the surgery group compared with the medical-therapy group.
The authors concluded that the quality-of-life improvements seen after surgery in this study are likely to be meaningful to patients with advanced PD.
PD SURG is the largest study to date comparing surgical to medical treatment in patients with PD.
Curing Insomnia ... And It's Not Counting Sheep
YOU need sleep like you need food, water and air. It is as natural as that. Yet, we humans willfully withhold sleep and deprive our bodies of its natural mechanism for rest and restoration.
Sometimes too much stress and lack of exercise can also cause sleep disturbance.
Somnipathy is a medical term for disorders of natural sleep patterns. Some sleep disorders are serious enough to interfere with normal physical, mental and emotional functioning. A polysomnogram test is used to identify sleep disorders.
The medical importance of sleep is recognised today with the rapidly increasing knowledge about sleep, including the discovery of Rapid Eye Movement (REM) sleep - which is a normal stage of sleep characterised by rapid movements of the eyes.
Indeed, sleep medicine is now a recognised subspecialty within internal medicine, family medicine, pediatrics, otolaryngology, psychiatry and neurology in North America and Europe.
Sleep disturbance is usually treated with powerful drugs like anxiolytics and sedatives that alter brain chemistry and have potential for addiction and a host of side effects.
Before resorting to this, it may be wise to look to nature and natural approaches to get a good night's sleep. The list below is by no means comprehensive but indicates the deep reservoir of know-how that helps kings and noblemen sleep over the ages.
- Simple regular exercise deepens sleep in young adults with or without sleep disorders. It makes you tired and hence go into a period of rest that involves various levels of sleep.
In addition, several studies show that exercise can improve sleep in older adults, too. Recent studies show that even the low-to- moderate Tai Chi and Tibetan Yoga practices enhance effective sleep in older persons.
Techniques aimed at relaxing muscles (progressive muscle relaxation and biofeedback) and quieting the mind (meditation) have been found to be effective treatments for insomnia.
Several studies show that regular meditation practised alone or as a part of Yoga practice, results in higher blood levels of melatonin, an important regulator of sleep.
- Acupuncture is often used in traditional Chinese medicine for the treatment of insomnia. It involves the insertion of very fine needles (sometimes in combination with electrical stimulus or with heat produced by burning specific herbs) into the skin at specific acupuncture points in order to influence the functioning of the body.
- Melatonin is a hormone made by a part of the brain called the pineal gland. It may help our bodies know when it is time to go to sleep and when to wake up.
The deficiency may cause sleep disorders, immune deficiency conditions, and depression.
Another hormone, progesterone, may also help post menopausal women get enough sleep.
- Sufficient intake of vitamins and minerals also play a role in preventing insomnia. People who don't have enough calcium have two sleep-related problems:
- difficulty falling asleep (due to low tissue calcium which causes irritability).
- muscle cramps at night (calcium and magnesium imbalance cause muscles to be in constant contraction).
Magnesium supplements may be helpful for relieving restless leg syndrome and treating insomnia.
This mineral is needed by every cell of the body for bone, protein, and fatty acid formation, making new cells, activating B vitamins, relaxing muscles, clotting blood, and forming ATP - the muscle's energy source.
Niacin is a member of the Vitamin B-complex. It is also known as Vitamin B3. Like most of the B-vitamins, niacin is primarily required for energy metabolism, specifically converting carbohydrates into energy.
Proper intake of niacin keeps the skin healthy. It can also be used therapeutically to control cholesterol levels, maintain proper circulation, act as an anti-inflammatory to ease arthritis and balance blood sugar levels for the prevention of diabetes.
It can be used to stimulate a healthy nervous system, easing symptoms of depression, anxiety and insomnia.
- Herbs like chamomile flowers are used in alternative medicine as an anti-inflammatory, antispasmodic, nervine, stomachic, tonic and vasodilatory.
It has a mild tranquilising effect (hence its use as a claming tea).
Passion flower is the herb of choice for treating insomnia.
It is a naturally grown medicinal herb, approved by the German Commission E in the treatment of insomnia and nervousness.
It is also used as a sedative in nervous disorders (including gastrointestinal complaints of nervous origin), difficulties in sleeping, and anxiety or restlessness.
It also seems to have an antispasmodic effect on smooth muscles within the body, including the digestive system, promoting digestion.
Valerian is a member of the Valerianaceae family. It has been used for thousands of years as a folk remedy, tranquiliser, and sedative for disorders such as restlessness, anxiety, and insomnia; it has been proven to be a safe and effective anti-anxiety agent and sedative.
Valerian is a common ingredient which is used as a mild sedative and sleep aid for nervous tension and insomnia.
- Nature is the most natural cure for sleep disorders. After all, a lot of sleep problems are the result of our deviation from the natural principles of living.
We don't hear of cavemen or animals being troubled by sleep disorders.
* Datuk Dr Rajen M. is a pharmacist with a doctorate in holistic medicine. Email him at health@po.jaring.my
(c) 2008 New Straits Times. Provided by ProQuest LLC. All rights Reserved.
Source: New Straits Times
Sometimes too much stress and lack of exercise can also cause sleep disturbance.
Somnipathy is a medical term for disorders of natural sleep patterns. Some sleep disorders are serious enough to interfere with normal physical, mental and emotional functioning. A polysomnogram test is used to identify sleep disorders.
The medical importance of sleep is recognised today with the rapidly increasing knowledge about sleep, including the discovery of Rapid Eye Movement (REM) sleep - which is a normal stage of sleep characterised by rapid movements of the eyes.
Indeed, sleep medicine is now a recognised subspecialty within internal medicine, family medicine, pediatrics, otolaryngology, psychiatry and neurology in North America and Europe.
Sleep disturbance is usually treated with powerful drugs like anxiolytics and sedatives that alter brain chemistry and have potential for addiction and a host of side effects.
Before resorting to this, it may be wise to look to nature and natural approaches to get a good night's sleep. The list below is by no means comprehensive but indicates the deep reservoir of know-how that helps kings and noblemen sleep over the ages.
- Simple regular exercise deepens sleep in young adults with or without sleep disorders. It makes you tired and hence go into a period of rest that involves various levels of sleep.
In addition, several studies show that exercise can improve sleep in older adults, too. Recent studies show that even the low-to- moderate Tai Chi and Tibetan Yoga practices enhance effective sleep in older persons.
Techniques aimed at relaxing muscles (progressive muscle relaxation and biofeedback) and quieting the mind (meditation) have been found to be effective treatments for insomnia.
Several studies show that regular meditation practised alone or as a part of Yoga practice, results in higher blood levels of melatonin, an important regulator of sleep.
- Acupuncture is often used in traditional Chinese medicine for the treatment of insomnia. It involves the insertion of very fine needles (sometimes in combination with electrical stimulus or with heat produced by burning specific herbs) into the skin at specific acupuncture points in order to influence the functioning of the body.
- Melatonin is a hormone made by a part of the brain called the pineal gland. It may help our bodies know when it is time to go to sleep and when to wake up.
The deficiency may cause sleep disorders, immune deficiency conditions, and depression.
Another hormone, progesterone, may also help post menopausal women get enough sleep.
- Sufficient intake of vitamins and minerals also play a role in preventing insomnia. People who don't have enough calcium have two sleep-related problems:
- difficulty falling asleep (due to low tissue calcium which causes irritability).
- muscle cramps at night (calcium and magnesium imbalance cause muscles to be in constant contraction).
Magnesium supplements may be helpful for relieving restless leg syndrome and treating insomnia.
This mineral is needed by every cell of the body for bone, protein, and fatty acid formation, making new cells, activating B vitamins, relaxing muscles, clotting blood, and forming ATP - the muscle's energy source.
Niacin is a member of the Vitamin B-complex. It is also known as Vitamin B3. Like most of the B-vitamins, niacin is primarily required for energy metabolism, specifically converting carbohydrates into energy.
Proper intake of niacin keeps the skin healthy. It can also be used therapeutically to control cholesterol levels, maintain proper circulation, act as an anti-inflammatory to ease arthritis and balance blood sugar levels for the prevention of diabetes.
It can be used to stimulate a healthy nervous system, easing symptoms of depression, anxiety and insomnia.
- Herbs like chamomile flowers are used in alternative medicine as an anti-inflammatory, antispasmodic, nervine, stomachic, tonic and vasodilatory.
It has a mild tranquilising effect (hence its use as a claming tea).
Passion flower is the herb of choice for treating insomnia.
It is a naturally grown medicinal herb, approved by the German Commission E in the treatment of insomnia and nervousness.
It is also used as a sedative in nervous disorders (including gastrointestinal complaints of nervous origin), difficulties in sleeping, and anxiety or restlessness.
It also seems to have an antispasmodic effect on smooth muscles within the body, including the digestive system, promoting digestion.
Valerian is a member of the Valerianaceae family. It has been used for thousands of years as a folk remedy, tranquiliser, and sedative for disorders such as restlessness, anxiety, and insomnia; it has been proven to be a safe and effective anti-anxiety agent and sedative.
Valerian is a common ingredient which is used as a mild sedative and sleep aid for nervous tension and insomnia.
- Nature is the most natural cure for sleep disorders. After all, a lot of sleep problems are the result of our deviation from the natural principles of living.
We don't hear of cavemen or animals being troubled by sleep disorders.
* Datuk Dr Rajen M. is a pharmacist with a doctorate in holistic medicine. Email him at health@po.jaring.my
(c) 2008 New Straits Times. Provided by ProQuest LLC. All rights Reserved.
Source: New Straits Times
Xel Pharmaceuticals Announces Successful Completion of Prototype Once-A-Week Huperzine A Transdermal Patch for Alzheimer's Disease
From the PharmaLive.com News Archive - Sep. 10, 2008
DRAPER, Utah--(BUSINESS WIRE)--Sep 10, 2008 - Xel Pharmaceuticals, Inc. announced today the completion of the development of its once-a-week Huperzine A transdermal patch for the treatment of Alzheimer's disease (AD). The prototype transdermal patch can deliver 400-800 mcg of Huperzine A per day for up to seven days. Huperzine A is a naturally occurring alkaloid found from the club moss Huperzia serrata that has been used for decades in China as a prescription medication for the treatment of dementia. Huperzine A is a potent, highly selective and reversible inhibitor of acetyl cholinesterase. Additionally, Huperzine A has anti-oxidative properties and possesses neuro-protective properties against glutamate that induce neuronal toxicity at the N-methyl-D-aspartate (NMDA) receptor.
Dr. Danyi Quan, Chief Scientific Officer of Xel, said, "The failure of recent Phase III clinical trials for AD treatment may cast some new doubt on that theory, as well as on other experimental drugs. In addition, some new Alzheimer drugs show potential risks including serious side effects. However, the clinical studies performed in China to date showed Huperzine A to be more effective than other cholinesterase inhibitors currently on the market, and the U.S. clinical Phase II trials with Huperzine A oral tablets conducted by the nation's leader in AD therapy, Dr. Paul Aisen, clearly demonstrated the efficacy and safety of Huperzine A in the treatment of patients with AD."
"In the past 10 years, there have been limits and some real difficulties in finding a good candidate from existing Western medicines to develop transdermal drug delivery systems. However, many drug candidates derived from botanic sources with proven safety and efficacy data are available for further development, which now has become a fast and effective way for us to select candidates for designing our advanced drug delivery systems. Huperzine A is one of our most promising and successful transdermal products. Its low therapeutic dose and molecular weight makes Huperzine A ideal for transdermal drug delivery. Our once-a-week transdermal patch is a clearly preferable treatment method to AD patients and caregivers. The prototype Huperzine A transdermal patch is ready for IND filing and further development," Dr. Quan added.
According to Mr. Wade Xiong, President and CEO of Xel, "We are delighted to announce the completion of the development of our prototype Huperzine A transdermal patch. Xel has two world-renowned scientists, Dr. Dinesh C. Patel and Dr. Danyi Quan, both of whom pioneer in transdermal delivery technology. As our Chairman of the Board, Dr. Patel also was the past founder of transdermal drug delivery pioneer TheraTech, Inc. (now Watson Pharmaceuticals). Xel's business strategy is to identify compounds having proven safety and efficacy, and to further develop advanced drug delivery systems in order to provide better delivery profiles, as well as patent protection. Currently, Xel has several co-development and licensing opportunities available for major pharmaceutical companies."
About Xel Pharmaceuticals, Inc.Xel Pharmaceuticals, Inc. is a specialized pharmaceutical company focused on merging advanced drug delivery technologies together with selected compounds having proven safety and efficacy from Chinese herbal medicine. Xel has developed and continues to research unique and patent-protected delivery technologies involving transdermal and controlled release delivery systems. For more information regarding this news release and Xel Pharmaceuticals, Inc., please visit the website.
DRAPER, Utah--(BUSINESS WIRE)--Sep 10, 2008 - Xel Pharmaceuticals, Inc. announced today the completion of the development of its once-a-week Huperzine A transdermal patch for the treatment of Alzheimer's disease (AD). The prototype transdermal patch can deliver 400-800 mcg of Huperzine A per day for up to seven days. Huperzine A is a naturally occurring alkaloid found from the club moss Huperzia serrata that has been used for decades in China as a prescription medication for the treatment of dementia. Huperzine A is a potent, highly selective and reversible inhibitor of acetyl cholinesterase. Additionally, Huperzine A has anti-oxidative properties and possesses neuro-protective properties against glutamate that induce neuronal toxicity at the N-methyl-D-aspartate (NMDA) receptor.
Dr. Danyi Quan, Chief Scientific Officer of Xel, said, "The failure of recent Phase III clinical trials for AD treatment may cast some new doubt on that theory, as well as on other experimental drugs. In addition, some new Alzheimer drugs show potential risks including serious side effects. However, the clinical studies performed in China to date showed Huperzine A to be more effective than other cholinesterase inhibitors currently on the market, and the U.S. clinical Phase II trials with Huperzine A oral tablets conducted by the nation's leader in AD therapy, Dr. Paul Aisen, clearly demonstrated the efficacy and safety of Huperzine A in the treatment of patients with AD."
"In the past 10 years, there have been limits and some real difficulties in finding a good candidate from existing Western medicines to develop transdermal drug delivery systems. However, many drug candidates derived from botanic sources with proven safety and efficacy data are available for further development, which now has become a fast and effective way for us to select candidates for designing our advanced drug delivery systems. Huperzine A is one of our most promising and successful transdermal products. Its low therapeutic dose and molecular weight makes Huperzine A ideal for transdermal drug delivery. Our once-a-week transdermal patch is a clearly preferable treatment method to AD patients and caregivers. The prototype Huperzine A transdermal patch is ready for IND filing and further development," Dr. Quan added.
According to Mr. Wade Xiong, President and CEO of Xel, "We are delighted to announce the completion of the development of our prototype Huperzine A transdermal patch. Xel has two world-renowned scientists, Dr. Dinesh C. Patel and Dr. Danyi Quan, both of whom pioneer in transdermal delivery technology. As our Chairman of the Board, Dr. Patel also was the past founder of transdermal drug delivery pioneer TheraTech, Inc. (now Watson Pharmaceuticals). Xel's business strategy is to identify compounds having proven safety and efficacy, and to further develop advanced drug delivery systems in order to provide better delivery profiles, as well as patent protection. Currently, Xel has several co-development and licensing opportunities available for major pharmaceutical companies."
About Xel Pharmaceuticals, Inc.Xel Pharmaceuticals, Inc. is a specialized pharmaceutical company focused on merging advanced drug delivery technologies together with selected compounds having proven safety and efficacy from Chinese herbal medicine. Xel has developed and continues to research unique and patent-protected delivery technologies involving transdermal and controlled release delivery systems. For more information regarding this news release and Xel Pharmaceuticals, Inc., please visit the website.
Treatment for Parkinson's Disease Examined
The PhD defended by Juan Carlos Gómez-Esteban at the University of the Basque Country analysed the results of the clinical research undertaken at the Movement Disorders Unit at Cruces Hospital since 1998. It involved a study of the most efficacious surgical operations undertaken and pharmaceutical drugs used to treat these disorders as well genetic studies carried out to date.
The field of movement disorders is one of the most complex branches of neurology. The volume of knowledge acquired is so large that it has needed a number of neurologists to sub-specialise in the matter and multidisciplinary units have been created to tackle problems such as the diagnosis of Parkinson’s Disease and of atypical Parkinsonisms, the choice of the most suitable surgical therapies and pharmaceutical drugs or the carrying out of genetic studies. Thus is 1998 the Movement Disorders Unit at Cruces Hospital in Bilbao was created with neurologists, neurosurgeons, neurophysiologists, anaesthetists, neuropsychologists and radiologists. Since its creation, more than 100 surgical operations have been carried out, the majority on patients with Parkinson’s Disease. Currently it is a centre of reference for functional surgery in the Autonomous Community of the Basque Country (CAPV), and even receives patients from other autonomous communities.
The PhD the neurologist Juan Carlos Gómez-Esteban presented at the University of the Basque Country (UPV/EHU), Results of clinical research at a movement disorders unit, brings together a number of different lines of research undertaken at the Cruces Hospital Movement Disorders Unit between 1998 and 2007. Mr Gómez-Esteban graduated in Medicine and General Surgery and his PhD, having received excellent ratings cum laude, was led by Dr. Juan José Zarranz Imirizaldu and Dr. Elena Lezcano García, both from the Department of Neurosciences of the Faculty of Medicine and Odontology at the UPV/EHU.
Results of the operations
The initial part of the thesis presented by Dr. Gómez-Esteban reviews the operations carried out at the Movement Disorders Unit; in concrete, analysing deep brain stimulation, a surgical procedure that acts on the nuclei deep inside the brain that do not function correctly in patients affected by different movement disorders. From his research he deduced that what is involved is an effective therapy for patients with advanced Parkinson’s and that the subthalamic nucleus (a small nucleus located at the base of the brain) is the surgical target that provides a more complete answer to an improvement in the symptoms of the illness. The operation involves implanting microelectrodes in this nucleus and which are controlled by a battery similar to a pacemaker.
Dr Gómez-Esteban states that the benefit of this type of operation for the symptoms affecting movement is similar to that obtained with dopaminergic pharmaceutical drugs (those containing dopamina precursors or behave similarly to them), with the exception of trembling, which responds better to surgical treatment rather than to pharmaceutical medicines. Another of the benefits of deep cerebral stimulation is the enhancement of the quality of life not only for the patient, but also for the carer. It also produces improvements in verbal memory, but changes in verbal fluency or executive functions have not been detected. Although initially symptoms of depression may be produced as a reaction related to patient expectation and to the surgical process itself, Dr. Gómez-Esteban affirms that, in the medium and long term, there is an improvement in the symptoms of depression.
This research also showed that patients suffering from the illness known as Parkinson-type multiple system atrophy as well as those with a specific mutation of the LRRK2-Dardarina gene, do not respond to surgery as well as those suffering from Parkinson’s of unknown cause or from other, hereditary Parkinson’s.
Genetic research: new mutations
Hereditary forms of Parkinson’s and dementia with Lewy bodies (a recently discovered illness previously confused with Parkinson’s or Alzheimer) are not frequent. In fact, Dr. Gómez-Esteban states that genetic defects associated with this last illness have not been found to date. However, the Movement Disorders Unit has discovered a new mutation in Parkinson’s Disease (a specific mutation in the gene known as alpha-synuclein), which is also associated with Lewy Body Dementia. Also notable is the fact that patients registering such a mutation do not have a primary sleep disorder, a reduction in the REM phases (in which dreams are produced) and NREM (in which dreams are not produced), which could even precede motor symptoms.
Sleep fragmentation, psychotic symptoms and analysis of pharmaceutical drugs
Another problem for Parkinson’s sufferers is the fragmentation of sleep or the impossibility of continuous sleep and nicturia (orinating frequently during the night). According to Dr. Gómez-Esteban, the drugs acting directly on the Dopamine receptors appear to improve nicturia, although not improving night time sleep nor the presence of daytime hypersomnia (difficulty in staying awake). 21.9% of patients studied at the Movement Disorders Unit suffer, moreover, from restless legs syndrome, which gives rise to a worsening in the quality of night time sleep and the quality of life.
Dr. Gómez-Esteban also reviewed research of Parkinson’s Disease patients who had psychotic symptom, such as visual hallucinations. The clinical trials undertaken at the Cruces Hospital point to the pharmaceutical drug Ziprasidona as being efficacious as an antipsychotic, having few adverse effects on the motor system that coordinate movement and regulates muscular tone.
The field of movement disorders is one of the most complex branches of neurology. The volume of knowledge acquired is so large that it has needed a number of neurologists to sub-specialise in the matter and multidisciplinary units have been created to tackle problems such as the diagnosis of Parkinson’s Disease and of atypical Parkinsonisms, the choice of the most suitable surgical therapies and pharmaceutical drugs or the carrying out of genetic studies. Thus is 1998 the Movement Disorders Unit at Cruces Hospital in Bilbao was created with neurologists, neurosurgeons, neurophysiologists, anaesthetists, neuropsychologists and radiologists. Since its creation, more than 100 surgical operations have been carried out, the majority on patients with Parkinson’s Disease. Currently it is a centre of reference for functional surgery in the Autonomous Community of the Basque Country (CAPV), and even receives patients from other autonomous communities.
The PhD the neurologist Juan Carlos Gómez-Esteban presented at the University of the Basque Country (UPV/EHU), Results of clinical research at a movement disorders unit, brings together a number of different lines of research undertaken at the Cruces Hospital Movement Disorders Unit between 1998 and 2007. Mr Gómez-Esteban graduated in Medicine and General Surgery and his PhD, having received excellent ratings cum laude, was led by Dr. Juan José Zarranz Imirizaldu and Dr. Elena Lezcano García, both from the Department of Neurosciences of the Faculty of Medicine and Odontology at the UPV/EHU.
Results of the operations
The initial part of the thesis presented by Dr. Gómez-Esteban reviews the operations carried out at the Movement Disorders Unit; in concrete, analysing deep brain stimulation, a surgical procedure that acts on the nuclei deep inside the brain that do not function correctly in patients affected by different movement disorders. From his research he deduced that what is involved is an effective therapy for patients with advanced Parkinson’s and that the subthalamic nucleus (a small nucleus located at the base of the brain) is the surgical target that provides a more complete answer to an improvement in the symptoms of the illness. The operation involves implanting microelectrodes in this nucleus and which are controlled by a battery similar to a pacemaker.
Dr Gómez-Esteban states that the benefit of this type of operation for the symptoms affecting movement is similar to that obtained with dopaminergic pharmaceutical drugs (those containing dopamina precursors or behave similarly to them), with the exception of trembling, which responds better to surgical treatment rather than to pharmaceutical medicines. Another of the benefits of deep cerebral stimulation is the enhancement of the quality of life not only for the patient, but also for the carer. It also produces improvements in verbal memory, but changes in verbal fluency or executive functions have not been detected. Although initially symptoms of depression may be produced as a reaction related to patient expectation and to the surgical process itself, Dr. Gómez-Esteban affirms that, in the medium and long term, there is an improvement in the symptoms of depression.
This research also showed that patients suffering from the illness known as Parkinson-type multiple system atrophy as well as those with a specific mutation of the LRRK2-Dardarina gene, do not respond to surgery as well as those suffering from Parkinson’s of unknown cause or from other, hereditary Parkinson’s.
Genetic research: new mutations
Hereditary forms of Parkinson’s and dementia with Lewy bodies (a recently discovered illness previously confused with Parkinson’s or Alzheimer) are not frequent. In fact, Dr. Gómez-Esteban states that genetic defects associated with this last illness have not been found to date. However, the Movement Disorders Unit has discovered a new mutation in Parkinson’s Disease (a specific mutation in the gene known as alpha-synuclein), which is also associated with Lewy Body Dementia. Also notable is the fact that patients registering such a mutation do not have a primary sleep disorder, a reduction in the REM phases (in which dreams are produced) and NREM (in which dreams are not produced), which could even precede motor symptoms.
Sleep fragmentation, psychotic symptoms and analysis of pharmaceutical drugs
Another problem for Parkinson’s sufferers is the fragmentation of sleep or the impossibility of continuous sleep and nicturia (orinating frequently during the night). According to Dr. Gómez-Esteban, the drugs acting directly on the Dopamine receptors appear to improve nicturia, although not improving night time sleep nor the presence of daytime hypersomnia (difficulty in staying awake). 21.9% of patients studied at the Movement Disorders Unit suffer, moreover, from restless legs syndrome, which gives rise to a worsening in the quality of night time sleep and the quality of life.
Dr. Gómez-Esteban also reviewed research of Parkinson’s Disease patients who had psychotic symptom, such as visual hallucinations. The clinical trials undertaken at the Cruces Hospital point to the pharmaceutical drug Ziprasidona as being efficacious as an antipsychotic, having few adverse effects on the motor system that coordinate movement and regulates muscular tone.
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