|
|
UCSF Gene Therapy Method Allays Parkinson’s Symptoms
Saturday, July 24, 2010
by Lauren HammitA novel technique created at UCSF to deliver a growth factor directly to brain cells has shown promising results in treating Parkinson’s symptoms and could enter human clinical trials as early as next year. The technique is part of an experimental treatment called gene therapy, which is considered a hopeful medical advance for neurodegenerative diseases such as Parkinson’s. Gene therapy involves introducing genetic material into a cell to cause the expression of a particular protein that can replace a missing or defective protein responsible for disease. The UCSF team demonstrated for the first time that the infusion system they designed successfully spread a targeted protein to critical regions in the primate brain. This resulted, on average, in a 50 percent improvement of symptoms that continued out to two years. “The approach is among the first shown to be beneficial to animals after they have already developed signs of Parkinson’s,” said Krystof Bankiewicz, MD, PhD, Kinetics Foundation Chair in Translational Research and professor of Neurological Surgery at UCSF. “Our ultimate goal is to reverse this disease in patients, and we hope this method will enable doctors to do exactly that.” Findings are published online and in the July 14, 2010, issue of the Journal of Neuroscience. In addition to an improvement in Parkinson’s symptoms, the treated animals also maintained a higher density of neurons that produce the brain chemical dopamine – the same neurons that disappear in Parkinson’s disease. Live imaging of the brain by positron emission tomography (PET) scanning, which has been used to gauge treatment effects in clinical studies of Parkinson’s, showed that those neurons remained active. “The scans enabled us to see where the protein went – and just as hoped, it had been taken up by neurons and transported along nerve fibers to where it was needed, the substantia nigra.” Bankiewicz said. Parkinson’s disease attacks thesubstantia nigra, which is a part of the brain that controls movement. A clinical trial is planned to test the safety of the method, according to the National Institutes of Neurological Disorders and Stroke, which funded this research. In a workup for the trial, the National Institutes of Health Rapid Access to Interventional Development (NIH RAID) program is supporting additional toxicity studies, as well as the production of clinical grade virus.
Top Ten Things to Know About Stem Cell Treatments
Saturday, July 10, 2010
There are different types of stem cellseach with their own purpose. |
| There are many different types of stem cells that come from different places in the body or are formed at different times in our lives. These include embryonic stem cells that exist only at the earliest stages of development and various types of tissue-specific or adult stem cells that appear during fetal development and remain in our bodies throughout life.
Our bodies use different types of tissue-specific stem cells to fit a particular purpose. Tissue-specific stem cells are limited in their potential and largely make the cell types found in the tissue from
which they are derived. For example, the blood-forming stem cells (or hematopoietic stem cells) in the bone marrow regenerate the blood, while neural stem cells in the brain make brain cells. A neural stem cell wont spontaneously make a blood cell and likewise a hematopoietic stem cell wont spontaneously make a brain cell. Thus, it is unlikely that a single cell type could be used to treat a multitude of unrelated diseases that involve different tissues or organs. Be wary of clinics that offer treatments with stem cells that originate from a part of the body that is different from the part being treated. |
2. A single stem cell treatment will not work on a multitude of unrelated diseases or conditions. |
| As described above, each type of stem cell fulfills a specific function in the body and cannot be expected to make cell types from other tissues. Thus, it is unlikely that a single type of stem cell treatment can treat multiple unrelated conditions, such as diabetes and Parkinsons disease. The underlying causes are very different and different cell types would need to be replaced to treat each condition. It is critical that the cell type used as a treatment be appropriate to the specific disease or condition.
Embryonic stem cells may one day be used to generate treatments for a range of human diseases. However, embryonic stem cells themselves cannot directly be used for therapies as they would likely cause tumors and are unlikely to become the cells needed to regenerate a tissue on their own. They would first need to be coaxed to develop into specialized cell types before transplantation. A major warning sign that a clinic may not be credible is when treatments are offered for a wide variety of conditions but rely on a single cell type. |
3. Currently, there are very few widely accepted stem cell therapies. |
| The range of diseases where stem cell treatments have been shown to be beneficial in responsibly conducted clinical trials is still extremely restricted. The best defined and most extensively used is blood stem cell transplantation to treat diseases and conditions of the blood and immune system, or to restore the blood system after treatments for specific cancers. Some bone, skin and corneal diseases or injuries can be treated with grafting of tissue that depends upon stem cells from these organs. These therapies are also generally accepted as safe and effective by the medical community. |
4. Just because people say stem cells helped them doesnt mean they did. |
| There are three main reasons why a person might feel better that are unrelated to the actual stem cell treatment: the placebo effect, accompanying treatments, and natural fluctuations of the disease or condition. The intense desire or belief that a treatment will work can cause a person to feel like it has and to even experience positive physical changes, such as improved movement or less pain. This phenomenon is called the placebo effect. Even having a positive conversation with a doctor can cause a person to feel improvement. Likewise, other techniques offered along with stem cell treatmentsuch as changes to diet, relaxation, physical therapy, medication, etc.may make a person feel better in a way that is unrelated to the stem cells. Also, the severity of symptoms of many conditions can change over time, resulting in either temporary improvement or decline, which can complicate the interpretation of the effectiveness of treatments. These factors are so widespread that without testing in a controlled clinical study, where a group that receives a treatment is carefully compared against a group that does not receive this treatment, it is very difficult to determine the real effect of any therapy. Be wary of clinics that measure or advertise their results primarily through patient testimonials. |
5. A large part of why it takes time to develop new therapies is that science itself is a long and difficult process. |
| Science, in general, is a long and involved process. Understanding what goes wrong in disease or injury and how to fix it takes time. New ideas have to be tested first in a research laboratory, and many times the new ideas dont work. Even once the basic science has been established, translating it into an effective medical treatment is a long and difficult process. Something that looks promising in cultured cells may fail as a therapy in an animal model and something that works in an animal model may fail when it is tried on humans. Once therapies are tested in humans, ensuring patient safety becomes a critical issue and this means starting with very few people until the safety and side effects are better understood. |
6. To be used in treatments, stem cells will have to be instructed to behave in specific ways. |
| Bone marrow transplantation is typically successful because we are asking the cells to do exactly what they were designed to do, make more blood. For other conditions, we may want the cells to behave in ways that are different from how they would ordinarily work in the body. One of the greatest barriers to the development of successful stem cell therapies is to get the cells to behave in the desired way. Also, once transplanted inside the body the cells need to integrate and function in concert with the bodys other cells. For example, to treat many neurological conditions the cells we implant will need to grow into specific types of neurons, and to work they will also have to know which other neurons to make connections with and how to make these connections. We are still learning about how to direct stem cells to become the right cell type, to grow only as much as we need them to, and the best ways to transplant them. Discovering how to do all this will take time. Be wary of claims that stem cells will somehow just know where to go and what to do to treat a specific condition. |
7. Just because stem cells came from your body doesnt mean they are safe. |
| Every medical procedure has risks. While you are unlikely to have an immune response to your own cells, the procedures used to acquire, grow and deliver them are potentially risky. As soon as the cells leave your body they may be subjected to a number of manipulations that could change the characteristics of the cells. If they are grown in culture (a process called expansion), the cells may lose the normal mechanisms that control growth or may lose the ability to specialize into the cell types you need. The cells may become contaminated with bacteria, viruses or other pathogens that could cause disease. The procedure to either remove or inject the cells also carries risk, from introducing an infection to damaging the tissue into which they are injected. |
8. There is something to lose by trying an unproven treatment. |
| Some of the conditions that clinics claim are treatable with stem cells are considered incurable by other means. It is easy to understand why people might feel they have nothing to lose from trying something even if it is unproven. However, there are very real risks of developing complications, both immediate and long-term, while the chance of experiencing a benefit is likely very low. In one publicized case, a young boy developed brain tumors as a result of a stem cell treatment. Participating in an unproven treatment may make a person ineligible to participate in upcoming clinical trials (see also number 9). Where cost is high, there may be long-term financial implications for patients, their families and communities. If travel is involved there are additional considerations, not the least of which is being away from family and friends. |
9. An experimental treatment offered for sale is not the same as a clinical trial. |
| The fact that a procedure is experimental does not automatically mean that it is part of a research study or clinical trial. A responsible clinical trial can be characterized by a number of key features. There is preclinical data supporting that the treatment being tested is likely to be safe and effective. Before starting, there is oversight by an independent group such as an Institutional Review Board or medical ethics committee that protect patients rights, and in many countries the trial is assessed and approved by a national regulatory agency, such as the European Medicines Agency (EMA) or the U.S. Food and Drug Administration (FDA). The study itself is designed to answer specific questions about a new treatment or a new way of using current treatments, often with a control group to which the group of people receiving the new treatment is compared. Typically, the cost of the new treatment and trial monitoring is defrayed by the company developing the treatment or by local or national government funding.Beware of expensive treatments that have not passed successfully through clinical trials.
Responsibly-conducted clinical trials are critical to the development of new treatments as they allow us to learn whether these treatments are safe and effective. The ISSCR supports participation in responsible clinical trials after careful consideration of the issues highlighted on this site and in discussion with a trusted physician.
For more information on clinical trials work click here |
10. Stem cell science is constantly moving forward. |
| Stem cell science is extraordinarily promising. There have been great advances in treating diseases and conditions of the blood system using blood-forming stem cells, and these show us just how powerful stem cell therapies can be. Scientists all over the world are researching ways to harness stem cells and use them to learn more about, to diagnose, and to treat various diseases and conditions. Every day scientists are working on new ways to shape and control different types of stem cells in ways that are bringing us closer to developing new treatments. Many potential treatments are currently being tested in animal models and some have already been brought to clinical trials. In February 2010 the British company ReNeuron announced it had been approved to conduct a Phase I clinical trial of a neural stem cell treatment for stroke. The first embryonic stem cell-based treatment for acute spinal cord injury is currently under review by the U.S. Food and Drug Administration (FDA) and will hopefully move into clinical trials soon. Although it is sometimes hard to see, stem cell science is moving forward. We are tremendously optimistic that stem cell therapies will someday be available to treat a wide range of human diseases and conditions. |
Spine Stimulation May Benefit Parkinson’s Disease Patients
Wednesday, June 23, 2010
By Steven Marsh
Patients who have been diagnosed with Parkinsons disease (PD) may have relief from symptoms associated with the condition in the near future, according to a study presented at the 2010 American Society for Stereotactical and Functional Neurosurgery.
In an effort to find potential treatments for individuals with the nervous system disorder, a team of researchers at Rhode Island Hospital conducted a series of exercises that stimulated the spinal cord on an animal model, which showed signs of PD. Because the findings displayed better motor function in the animal, the investigators tested the treatment with spinal cord simulation on a male patient aged 82 years.
While the individual wasn't receiving any form of medication as treatment for the disorder, researchers used different frequencies of stimulation to determine if a human would experience similar results compared to the animal model.
The researchers discovered that high stimulation frequencies made it easier for the patient to walk, while low frequencies worsened PD side effects.
While the results of thes tudy did give investigators some insight as to how to treat PD patients, clinical trials with a larger group of patients would be more beneficial to developing treatment.
Finding therapies for this disorder is growing in interest throughout the medical world, as QR Pharma and Massachusetts General Hospital have launched research to determine a way to block a protein associated the development of PD.ADNFCR-1960-ID-19845071-ADNFCR
The Pharmacist's Perspective on Treatment of Early-Stage Parkinson's Disease
Thursday, June 10, 2010
Jack J. Chen, PharmD, BCPS, CGP
The management of Parkinson'sdisease (PD) is complex and involves nonpharmacologic and pharmacologicinterventions for motor and nonmotor symptoms (see accompanying articleby Dr. Simuni). The aim of this article is to provide a greaterunderstanding of PD, treatment risks and benefits, and new developmentsin treatment approach that will allow clinicians, pharmacists, andallied healthcare personnel to better educate and care for patients withPD.
As PD progresses from early to advanced stages, medicationadjustments and increased numbers of medications should be expected.This article will focus on pharmacotherapy interventions for early-stagePD with an emphasis on safety and drug interactions. A discussion aboutearly interventions in PD, outcomes, and healthcare costs is availableelsewhere.[1] Discussions regarding advanced stage PD, management ofmotor complications, and pharmacotherapies for nonmotor symptoms of PDare beyond the scope of this article and are also availableelsewhere.[2]
The Patient With Early-Stage PD
An individualwith early-stage PD who has been recently diagnosed may present withmotor symptoms and absence of functional impairment or mild functionalimpairment (eg, clumsiness of the hands, mild deterioration inperformance of sports activities, a bothersome tremor, worsening ofhandwriting). An untreated patient with early-stage PD will have aUnified Parkinson's Disease Rating Scale (UPDRS) score of 20 to 30.
Thecurrent pharmacologic management paradigm for early-stage PD consistsof initiating 1 drug (ie, monotherapy) to provide symptomatic benefit.Drug therapy is typically initiated to address functional impairment.However, with the publication of the Attenuation of Disease progressionwith Azilect Given Once-daily (ADAGIO) study data, initiation ofrasagiline in recently diagnosed patients with early PD presentingwithout functional impairment is a plausible approach.
Inearly-stage PD, monoamine oxidase type B (MAO-B) inhibitors, dopamineagonists, and levodopa (with a decarboxylase inhibitor such ascarbidopa) all provide a sufficient magnitude of therapeutic effect. Inaddition to providing relief of tremor, rigidity, and/or slowness ofmovement, pharmacotherapy can also improve nonmotor symptoms such asfatigue in early PD and can improve experiences of daily living. Ifother symptoms such as constipation, depression, sexual dysfunction, andsleep disorders are present, adjunctive therapies that specificallytarget the symptom should also be considered.
Pharmacotherapy forEarly-Stage PD: Safety, Side Effects, Drug Interactions
Drugsafety and treatment-emergent side effects play a major role in guidingthe selection and adjustment of pharmacotherapy in PD. Healthcareprofessionals involved in the pharmacotherapy management anddistribution spectrum of PD should be concerned about the overall safetyof the medications in this population, the safety of polypharmacyregimens and their necessity (or lack thereof), drug interactions, andeducation of the patient and family about benefits and risks of themedication regimen. Pharmacists, in particular, are traditionally morefocused on drug safety and interactions as well as on providinginstructions on proper use of medications.
Levodopa
Levodopaprovides a robust magnitude of symptom relief effects. In patients withearly PD, common side effects of levodopa include nausea andsomnolence. Of note, hallucinations and psychosis are more common inpatients with advanced stage PD. There is concern about the gradualemergence of motor complications (such as dyskinesias and fluctuations)associated with dose escalation and treatment duration. Motorcomplications can arise quickly (within a few months) or slowly (after ayear or more). Although there are risk factors (eg, levodopa dose andtreatment duration, younger age), no method has been found to predictwhich patients will experience motor complications.
Thedevelopment of levodopa-associated motor complications has a significantimpact on clinicians, patients, and healthcare resources. Motorcomplications can be a challenge for clinicians to manage, can impairpatient health-related quality of life, and can increase direct healthcosts. Independent researchers and pharmaceutical manufacturers havedevoted time and resources toward understanding the pathophysiology ofmotor complications and developing interventions that have specificefficacy for motor complications (eg, apomorphine, entacapone,rasagiline, selegiline oral disintegrating tablets, and deep brainstimulation). Eventually all patients with PD will be prescribedlevodopa; however, in patients with early PD, other medications areavailable to provide adequate symptom relief without the risk for motorcomplications.
Pramipexole, ropinirole, and rasagiline are alsoindicated as monotherapy for PD. Clinicians and patients should engagein discussions about the relative risks and benefits of levodopatherapy, and patients should be allowed to make informed decisions.
DopamineAgonists
The dopamine agonists (pramipexole, ropinirole) providesufficient symptomatic effects for patients with early-stage PD and areless likely to cause motor complications. Side effects that areencountered by patients with early PD include nausea, somnolence, edemaof the extremities, orthostatic hypotension, and impulse controldisorders (ICDs). Of note, hallucinations may occur in patients withearly PD, but are more common in advanced stage PD or patients withcognitive impairment.
Postmarketing recognition of the potentialfor dopamine agonist-induced ICDs has attracted much concern amongclinicians who treat PD. ICDs can be a source of financial and familialstrain for the patient. Common examples include excessive gambling,preoccupation with pornography, overindulgence in purchasing unnecessaryitems, excessive hobbyism, and preoccupation with Internet activities.The prospect of this potentially disruptive side effect should becommunicated to the patient and family. Dopamine agonist-associated ICDsare not dose related and can also develop in patients receiving lowdaily doses for restless legs syndrome.
MAO-B Inhibitors
TheMAO-B inhibitors (rasagiline, selegiline) provide modest symptomaticrelief in patients with early PD. Of the available MAO-B inhibitors,rasagiline is the only one with labeling approved by the US Food andDrug Administration for monotherapy in PD. In addition, data from theADAGIO study (a large, randomized, controlled trial) suggest that earlyinitiation of rasagiline in patients with PD and the absence offunctional impairment confer more benefit than delaying therapy.
Rasagilineis well tolerated in patients with early PD. Treatment-emergent sideeffects are nonspecific and include flulike weakness and asthenia.Overall, rasagiline is notable for its lack of dopaminergic side effects(eg, nausea, orthostasis, somnolence). Postmarketing data indicate thatrasagiline can be safely administered without regard to meal content oftyramine (eg, in foods such as aged cheeses, red wine, sauerkraut).Based on clinical pharmacology studies, tyramine restriction is nolonger required or advocated by the FDA when rasagiline is initiated.Likewise, sympathomimetic amines (eg, ephedrine, phenylephrine,phenylpropanolamine, pseudoephedrine) and local anesthesia withsympathomimetic vasoconstrictors can be administered concomitantly.Although the concurrent use of antidepressants (with serotonergicactivity) is not contraindicated, benefits should be weighed against thepotential for serotonin syndrome. The STACCATO study is underway tobetter define the potential occurrence of serotonin syndrome withrasagiline and antidepressants.[3]
Patient and Family Education
Patientand family education is critical for the safe and successful use ofmedications in patients with PD. The patient/family should be counseledabout the adverse effects that are most likely to occur and when toreport them to the prescriber. For example, ICDs such as Internetgambling could go undetected by family and unreported by patients andresult in serious financial complications. Nausea, common with levodopaand dopamine agonists, is uncomfortable for patients, and in somecircumstances, may cause discontinuation of therapy prematurely ifpatients are not informed in advance about how to manage the effect. Thesame is true for other adverse effects such as somnolence andorthostatic hypotension. Educating patients and family members aboutpotential treatment-emergent side effects and the importance of seekingassistance can mitigate premature abandonment of the therapy and preventthe side effect from becoming more severe.
Patients and familiesshould be counseled about the drug's expected time to onset andresponse. Levodopa symptomatic benefit will be noted almost immediately(within a few doses or days). Dopamine agonists require initiation at alow (subtherapeutic) dose with gradual titration to a maintenance dose.This is done to minimize side effects. Thus, onset of a noticeableimprovement usually takes more than 2 weeks. The onset of noticeableimprovement with rasagiline may take several weeks, and the full effectmay not be seen for up to 8 to 12 weeks.
Lack of awarenessregarding a realistic onset of effect can lead to medication abandonment(because of the belief that the drug is ineffective) and polypharmacy(if other agents are prescribed to treat symptoms that have not yetresponded to the initial agent).
Patients and families should becounseled about the risks of self-discontinuing a drug for PD. Aworsening of motor symptoms would occur, and in some cases,discontinuation effects such as agitation, anxiety, diaphoresis,dysphoria, insomnia, or neuroleptic malignant syndrome may occur.
Parkinson'sdisease is a lifelong neurologic disorder. Patients will be onpharmacotherapy for the rest of their lives and will have manyencounters with professionals in healthcare. Early-stage, mildlyimpairing PD will progress over time to advanced stages, with severemotor impairment and nonmotor deficits. For patients with early-stage PDand their families, dealing with the diagnosis, learning about PD andits prognosis, and accepting the need for lifelong therapy can beoverwhelming. Clinicians, pharmacists, and allied healthcare personnelcan help patients and families dealing with PD by ensuring that theyreceive adequate medication information at the time a new prescriptionis written and again when it is dispensed. Patients should be assessedfor side effects, and the need for ongoing monitoring of medicationefficacy and potential side effects should be discussed with the family.
Summary
Patientswith early-stage PD will have many encounters with healthcareprofessionals during their lifetime. A better understanding of the motorand nonmotor symptoms of PD, risks and benefits of PD medications(Table), and drug-related complications will allow clinicians,pharmacists, and allied health professionals to better educate andmanage patients. Thoughtful consideration about the initiation ofpharmacotherapy for early-stage PD and information on realisticexpectations of efficacy and side effects can help prevent therapyabandonment and improve clinician-patient management of PD.
Supportedby an independent educational grant from Teva Neuroscience.
Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomi
Wednesday, June 02, 2010
Bxarone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, TolosaE, Weintraub D.
Department of Neurological Sciences, Universityof Naples Federico II and IDC Hermitage Capodimonte, Naples, Italy.barone@unina.it
Abstract
BACKGROUND: Depression is commonin patients with Parkinson's disease, but evidence on the efficacy ofantidepressants in this population is lacking. Because depression inpatients with Parkinson's disease might be related to dopaminergicdysfunction, we aimed to assess the efficacy of the dopamine agonistpramipexole for treatment of depressive symptoms in patients withParkinson's disease. METHODS: We did a 12-week randomised, double-blind,placebo-controlled (1:1 ratio) trial of pramipexole (0.125-1.0 mg threetimes per day) compared with placebo in patients with mild-to-moderateParkinson's disease. Patients from 76 centres in 12 European countriesand South Africa were included if they were on stable antiparkinsoniantherapy without motor fluctuations and had depressive symptoms (15-itemgeriatric depression scale score > or =5 and unified Parkinson'sdisease rating scale [UPDRS] part 1 depression item score > or =2).Patients were randomly assigned by centre in blocks of four by use of arandomisation number generating system. Clinical monitors, the principalinvestigator, and patients were masked to treatment allocation. Theprimary endpoint was change in Beck depression inventory (BDI) score andall treated patients who had at least one post-baseline efficacyassessment were included in the primary analysis. We also did apre-specified path analysis with regression models to assess therelation between BDI and UPDRS part 3 (motor score) changes. This trialis registered with ClinicalTrials.gov, number NCT00297778, and EudraCT,number 2005-003788-22. FINDINGS: Between March, 2006, and February,2008, we enrolled 323 patients. Of 296 patients randomly assigned topramipexole or placebo, 287 were included in the primary analysis: 139in the pramipexole group and 148 in the placebo group. BDI scoresdecreased by an adjusted mean 5.9 (SE 0.5) points in the pramipexolegroup and 4.0 (0.5) points in the placebo group (difference 1.9, 95% CI0.5-3.4; p=0.01, ANCOVA). The UPDRS motor score decreased by an adjustedmean 4.4 (0.6) points in the pramipexole group and 2.2 (0.5) points inthe placebo group (difference 2.2, 95% CI 0.7-3.7; p=0.003, ANCOVA).Path analysis showed the direct effect of pramipexole on depressivesymptoms accounted for 80% of total treatment effect (p=0.04). Adverseevents were reported in 105 of 144 patients in the pramipexole group and101 of 152 in the placebo group. Adverse events in the pramipexolegroup were consistent with the known safety profile of the drug.INTERPRETATION: Pramipexole improved depressive symptoms in patientswith Parkinson's disease, mainly through a direct antidepressant effect.This effect should be considered in the clinical management of patientswith Parkinson's disease. Copyright 2010 Elsevier Ltd. All rightsreserved.
|