ANA: No Benefit for Quinacrine in CJD

ANA: No Benefit for Quinacrine in CJD

By Richard Robinson, Contributing Writer, MedPage Today Published: October 15, 2009 Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit for reading medical news

Action Points --------------------------------------------------------------------------------

¦Explain to interested patients that sporadic CJD is a progressive brain disease due to accumulation and spread of misfolded protein.

¦Explain that the drug quinacrine did not extend survival in patients with CJD despite its ability to eliminate prions in vitro.

¦Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

BALTIMORE -- The first U.S. treatment trial for sporadic Creutzfeldt-Jakob disease (CJD) has shown that quinacrine does not extend survival compared with placebo, a researcher reported here.

Nonetheless, the trial represents progress in understanding the natural history of CJD and provides researchers with a prototype for future trials, according to lead investigator Michael Geschwind, MD, PhD, Assistant Professor of Neurology at the University of California San Francisco, and a researcher at the Memory and Aging Center there.

Geschwind described the study at the annual meeting of the American Neurological Association.

CJD is a prion disease, caused by accumulation of misfolded prion proteins in neurons: the misfolded proteins then cause others to misfold, spreading the pathology.

A small percentage of CJD cases are due to mutation in the prion gene, but most cases are sporadic. There are approximately 300 new cases of sporadic CJD in the U.S. every year. It is rapidly progressive, with few patients surviving more than a year after onset.

Quinacrine is an antimalarial drug that can eliminate prions in cell cultures. Open-label treatment in a handful of patients seemed to suggest a benefit for survival, so Geschwind developed a protocol for a blinded trial.

"We struggled with whether it was ethical to do a placebo-controlled trial in a uniformly fatal disease, but really that's the only way we are going to get the correct answer," Geschwind said. Using historical controls was not an option, because there was too much variability among samples.

Fifty-four patients with confirmed sporadic CJD were randomized to either quinacrine or placebo for two months, after which they could elect to switch to open-label quinacrine. The main outcome measure was survival from randomization, with follow-up at months two, six, and 12.

"Unfortunately, there was no survival difference between the two groups, either at two months or over the course of the disease," he said.

But the trial nonetheless produced important results. "It was not a complete loss. We know we can do a trial in a rapidly progressive, fatal disease. We now have very quantifiable data on natural history, so when the next drug becomes available, we'll be able to do a trial very quickly. And I am confident we will find more compounds."

For effective therapy, Geschwind said, "We are probably going to need more than one drug -- one to help clearance, one to prevent conversion of normal to abnormal protein, and perhaps even one to diminish the level of normal protein itself, so there is less substrate for the abnormal protein. We and other labs are screening compounds for these effects."

Geschwind reported no financial conflicts. The study was funded by the National Institutes of Health.

Primary source: American Neurological Association Source reference: Geschwind MD, et al "The first U.S. treatment trial for sporadic CJD" ANA 2009; Abstract T-71.


http://www.medpagetoday.com/Neurology/GeneralNeurology/16447


http://www.neuroprion.org/en/video_090711_10.html



View of NCT00183092 on 2009_03_10 ClinicalTrials Identifier: NCT00183092 Updated: 2009_03_10 Descriptive Information Brief title CJD (Creutzfeldt-Jakob Disease) Quinacrine Study

Official title Novel Therapeutics For Prion Diseases: A Randomized, Double-Blinded, Placebo-Controlled Study of the Efficacy of Quinacrine in the Treatment of Sporadic Creutzfeldt-Jakob Disease

Brief summary The purpose of this clinical trial is to determine the effectiveness of the medication quinacrine on survival in sporadic Creutzfeldt-Jakob disease (sCJD).

Detailed description Creutzfeldt-Jakob disease (CJD)is a rapidly progressive, invariably fatal and untreatable neurodegenerative disease with a mean duration of about eight months. Beyond the debilitating cognitive and motor deficits that accompany CJD, the difficulty in treating behavioral and mood disturbances and the rapidity of its course compound its tragedy. Recent results from experiments show that, at physiological concentrations, the anti-malarial drug quinacrine permanently clears abnormal prion proteins from cell culture. The demonstrated efficacy of quinacrine in cell culture, its relative safety and well known side-effects in the clinical setting, and the universal fatality of CJD justify quinacrine as an immediate candidate for the treatment of CJD.

The purpose of this clinical trial is to determine the efficacy of the medication quinacrine on survival in sporadic CJD (sCJD). This will be accomplished by bringing approximately 60 patients with probable or definite sCJD over approximately three years to UCSF for evaluation and initiation of a randomized, double-blinded, placebo-controlled (delayed treatment start) treatment study of quinacrine. Each patient will have a 50:50 chance of being placed on quinacrine or placebo upon study enrollment; however, all patients will be offered quinacrine after two months. Prior to study enrollment, patients will have a comprehensive clinical assessment to confirm the diagnosis of sCJD. Participants will come to UCSF for initial evaluation, potential study enrollment and, if possible, return to UCSF for follow-up at two and twelve months. Patients will receive telephone follow-up (every 2 weeks for the first two months and monthly thereafter) and local blood and testing to monitor for possible medication toxicity.

Phase Phase 2 Study type Interventional Study design Treatment Study design Randomized Study design Double Blind Study design Placebo Control Study design Parallel Assignment Study design Efficacy Study Primary outcome Survival from the time of randomization Secondary outcome Scores on functional scales, neurological exam and functional testing Condition Creutzfeldt-Jakob Disease Intervention Drug: Quinacrine

Reference Citation: Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83. Review. MEDLINE: 9811807 Reference Citation: Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9836-41. MEDLINE: 11504948 Reference Citation: Scoazec JY, Krolak-Salmon P, Casez O, Besson G, Thobois S, Kopp N, Perret-Liaudet A, Streichenberger N. Quinacrine-induced cytolytic hepatitis in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2003 Apr;53(4):546-7. No abstract available. MEDLINE: 12666126 Reference Citation: Wallace DJ. Is there a role for quinacrine (Atabrine) in the new millennium? Lupus. 2000;9(2):81-2. No abstract available. MEDLINE: 10787002 Reference Citation: Engel GL. Quinacrine effects on the central nervous system. JAMA. 1966 Aug 8;197(6):515. No abstract available. MEDLINE: 5952734

URL


http://memory.ucsf.edu


URL

http://ind.universityofcalifornia.edu/


See also UCSF Memory & Aging Center

See also UCSF Institute for Neurodegenerative Diseases

Recruitment Information Status Active, not recruiting Start date 2005-04 Criteria Inclusion Criteria: - Diagnosis of probable or definite sCJD: Definite--biopsy confirmed sCJD; Probable--a progressive dementia with either a typical EEG or a typical MRI consistent with sCJD, and at least two of the following clinical features: myoclonus, pyramidal or extrapyramidal signs, visual symptoms, cerebellar signs, akinetic mutism, other focal higher cortical neurologic signs (e.g. neglect, apraxia, aphasia) - 18 years of age or older - Able to swallow - Able to follow simple one-step commands - Have had a brain MRI within 6 months and an EEG within 3 months ruling out other etiologies such as masses, strokes, or non-convulsive status epilepticus - Consent to autopsy in the event of their death during or after the study

Exclusion Criteria: - History of other significant or life-threatening disease, including: cancer; end-stage liver or renal disease; severe heart disease - History of other disease requiring regular supportive care - Liver disease - Active alcoholism - Bone marrow suppression - Severe hypotension - Severe psoriasis - Poorly controlled diabetes - Women who are pregnant or breast-feeding - Men, or women of childbearing age, not practicing reliable contraception - Serious allergies to quinacrine or other acridines - Current or recent use of quinacrine (within 6 months) - < 18 years of age - Any other contraindication to taking quinacrine - Genetic form of prion disease is identified prior to study enrollment - Current use of anti-arrhythmics (at discretion of investigator) - G6PD (Glucose 6-Phosphate Dehydrogenase) deficiency (at discretion of investigator)

Gender Both Minimum age 18 Years Healthy volunteers No Administrative Data Organization name National Institute on Aging (NIA) Organization study ID IA0083 Secondary ID AG21601-03 Lead sponsor National Institute on Aging (NIA) Health Authority United States: Food and Drug Administration



http://clinicaltrials.gov/archive/NCT00183092/2009_03_10



http://clinicaltrials.gov/show/NCT00183092




Saturday, June 13, 2009

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009


http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html




Tuesday, August 11, 2009

Characteristics of Established and Proposed Sporadic Creutzfeldt-Jakob Disease Variants

Brian S. Appleby, MD; Kristin K. Appleby, MD; Barbara J. Crain, MD, PhD; Chiadi U. Onyike, MD, MHS; Mitchell T. Wallin, MD, MPH; Peter V. Rabins, MD, MPH

Background: The classic Creutzfeldt-Jakob disease (CJD), Heidenhain, and Oppenheimer-Brownell variants are sporadic CJD (sCJD) phenotypes frequently described in the literature, but many cases present with neuropsychiatric symptoms, suggesting that there may be additional sCJD phenotypes.

Objective: To characterize clinical, diagnostic, and molecular features of 5 sCJD variants.

Design: Retrospective analysis.

Setting: The Johns Hopkins and Veterans Administration health care systems.

Participants: Eighty-eight patients with definite or probable sCJD.

Main Outcome Measures: Differences in age at onset, illness progression, diagnostic test results, and molecular subtype.

Results: The age at onset differed among sCJD variants (P=.03); the affective variant had the youngest mean age at onset (59.7 years). Survival time (P
.001) and the time to clinical presentation (P=.003) differed among groups. Patients with the classic CJD phenotype had the shortest median survival time from symptom onset (66 days) and those who met criteria for the affective sCJD variant had the longest (421 days) and presented to clinicians significantly later (median time from onset to presentation, 92 days; P=.004). Cerebrospinal fluid analyses were positive for 14-3-3 protein in all of the affective variants, regardless of illness duration. Periodic sharp-wave complexes were not detected on any of the electroencephalography tracings in the Oppenheimer-Brownell group; basal ganglia hyperintensity was not detected on brain magnetic resonance imaging in this group either. All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.

Conclusions: The classic CJD phenotype and the Heidenhain, Oppenheimer-Brownell, cognitive, and affective sCJD variants differ by age at disease onset, survival time, and diagnostic test results. Characteristics of these 5 phenotypes are provided to facilitate further clinicopathologic investigation that may lead to more reliable and timely diagnoses of sCJD.

Arch Neurol. 2009;66(2):208-215

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COMMENT

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http://creutzfeldt-jakob-disease.blogspot.com/2009/08/characteristics-of-established-and.html



Thursday, September 24, 2009

Suit: Meatpacker used `downer' cows for 4 years TO FEED OUT CHILDREN ALL ACROSS THE NATION, the most high risk for mad cow disease


http://downercattle.blogspot.com/2009/09/suit-meatpacker-used-downer-cows-for-4.html


Monday, May 11, 2009

Rare BSE mutation raises concerns over risks to public health



http://bse-atypical.blogspot.com/2009/05/rare-bse-mutation-raises-concerns-over.html







TSS