2004 - Memantine and HD
"...remember that results in the clinic are always messier than those coming from a lab. People’s brains are (orders of magnitude) more complex than cells in a culture dish. "
Glutamate Blockers in the Lab and in the Clinic
Purity in the Lab
Excitotoxicity is the descriptive word used for one of the mechanisms that scientists believe contributes to nerve injury and cell death in Huntington’s (and other neurodegenerative diseases). Because excess nerve stimulation from glutamate is thought to promote this damage; a legitimate medical goal is to block glutamate (over) action.
In overabundance, glutamate is toxic to all brain cells, but especially so for neurons that are most damaged in HD (J.Dubinsky et al, Experimental Neurology 189. 2. 2004). The glutamate receptor molecule is also a calcium ion channel. Excess calcium leads to nerve injury.
Important for potential Huntington’s treatment, Dubinsky showed that nerve damage in the lab is decreased by drug molecules that block this glutamate action.
Clutter in the Clinic
Memantine is a (glutamate receptor blocker) drug that is already being prescribed in the clinic. It is an FDA approved drug for use in Alzheimer’s and is paid for by most medical insurance carriers if the doctor confirms a “dementia” diagnosis.
A few weeks ago, the results of a study using memantine in Huntington’s was published (A. Beister, M. Gerlach, J. Neural Transmitters (2004) (Suppl) 68 117-122). This study was done in Germany and involved 27 HD participants who took the drug for 2 years. This study was “open label” and not placebo-controlled: each participant and doctor knew that memantine was being used. The drug was given in doses similar to that used in Alzheimer’s.
The results are messy, but promising. There is no pure “take home” message: But remember that results in the clinic are always messier than those coming from a lab. People’s brains are (orders of magnitude) more complex than cells in a culture dish.
The tests used to measure potential benefit in Huntington’s participants fell short of the full battery of tests used in the United Huntington’s Disease Rating Scale (UHRDS). This latter test is considered the “gold standard: So the results can be considered less valid than those obtained through more exhaustive testing.
With these limitations, they then compared disease progression in the memantine-treated group to “predicted” progression. Predicted progression (using UHRDS measures) has been established by the Huntington Study Group. Or said another way, they used “historical” controls for comparison.
While historical controls may be valid, the German investigators were not measuring the same parameters as those measured by HSG in the historical control group. So they may have been trying to compare “apples to oranges”. Basing conclusions on the comparison of their progression measures to UHDRS is problematic and messy.
But, within the limitation of non-perfect comparisons, they observed slowing of disease progression by motor, cognitive, and functional capacity measures when compared to historical controls. Most of the benefit was not present till the second year of the study when no progression was observed in several testing parameters. If (and it is a big if) their quantitative comparisons are reliable; the benefit seen is HD is much higher than that seen in Alzheimer’s.
Comments
This is not a great study. It is downright messy and doesn’t “for sure” prove that memantine helps. It is more of the same for the HD community: Memantine is yet another agent in this all-too-familiar HD dilemma. Benefit is suggested but not proved for several potentially beneficial drugs.
A big question in the HD community is whether HD people and their doctors should wait for definitive clinical trials. It is a fact that, despite the uncertainty, many in the HD community will choose to use memantine and/or other available agents of potential benefit. Who can blame them? In so doing they believe they are “taking their best shot” at HD. Others in the HD community believe this proactive stance is an abuse and ridicule the users for “jumping the gun” before proof; even though researchers believe that proof will be long years in coming.
I don’t know who is right and who is wrong. For sure we all have our opinions. But in the end, nobody knows. But either way, proactive or conservative, HD people should have choice. After all, it is HD people who are facing irreversible brain damage. Isn’t it understandable that some may not want to wait for the years of time that it is taking for gold standard clinical trials?
HD people, the doctors, the researchers all are frustrated by these circumstances. But the major stakeholders in this situation are HD people. HD people face this terminal and devastating disease for which there is no recommended treatment. This is in the setting of clinical trial proof being years away. Taking nothing translates to sure irreversible brain damage. Taking available agents that might help is the only present option. Some will choose this option, some will not.
Given this situation choice is a patient right, and one that should be honored without ridicule.
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Source: LaVonne Veatch Goodman, M.D.
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