Yesterdays Public Relation announcement on the Dr. Schneider's GM1 ganglioside treatment of Parkinson's disease was an early pilot study for the safety and efficacy of using GM1. The initial trial consisted of 10 Parkinson's patients excluding those with the presence of signs indicative of progressive supranuclear palsy or suspected Parkinson-plus syndromes, focal or lateralized abnormalities on neurologic examination (other than parkinsonism), or history of any of the following: infective or inflammatory brain disease; alcohol or drug abuse; recent acute myocardial infarct; severe psychiatric disturbance; hepatic, renal, hematologic, or endocrine disease; multiple episodes of head trauma associated with sustained loss of conciousness; or Guillain-Barre syndrome (GBS). All patients received an IV loading dose if 1,000 mg GM1 administered over a 30 minute period. Patients were sent home with a 4-week supply of GM1, which they were trained to administer to themselves by subcutaneous injection. They returned each 4 weeks for testing and were sent home with another 4 week supply until the 12th week when they were sent home with a 6 week supply. Each patient self-administered two injections/day for a total daily dose of 200 mg of GM1. Two patients dropped out of the study. Eight patients completed the full 18-week course of treatment. When the individual items from UPDRS motor examination were analyzed, most of the improvements resulted from decreased rigidity and bradykinesia scores. Several patients reported improvements in walking ability, ability to dress themselves, overall level of energy, and manual dexterity. GM1 was provided by Fidia Pharmaceutical Corporation. ----------------- Start of Press Release ------------------------ 06/22 0806 CLINICAL TRIALS BEAR OUT PROMISE OF NEW ... A pilot clinical trial showed encouraging evidence that the drug GM1 ganglioside is effective at substantially reducing some of the functional impairments caused by Parkinson's disease. Those results, reported in the June issue of Neurology, are the basis for controlled trials being conducted at Medical College of Pennsylvania and Hahnemann University (MCPHU), Philadelphia. Unlike two controversial Parkinson's procedures recently under public discussion -- fetal cell transplant and pallidotomy surgery -- GM1 ganglioside is non-invasive, self-administered and potentially more accessible to Parkinson's patients. The drug appears to enhance the brain's ability to produce the key neurotransmitter dopamine; it is the lack of dopamine that leads to the tremors, rigidity and cognitive problems that mark Parkinson's. "Though the precise mechanism is not clear, GM1 ganglioside may rescue damaged dopamine neurons, stimulate them to repair themselves, promote growth of new dopamine terminals on the neurons -- and perhaps even stimulate remaining dopamine neurons to produce more than their normal amount of dopamine," said the study's lead author, Jay Schneider, Ph.D., professor of anatomy, neurobiology and neurology, MCPHU. Dr. Schneider and his colleagues reported that the functional improvements brought about by the drug continued for the duration of the study. Improvements in motor skills and activities-of-daily-living included decreased rigidity and bradykinesia (abnormally slow movement); reduced time required to perform physical tasks; greater ease in walking and dressing, and an increased energy level. Cognitively, the patients were less distractible. Parkinson's disease, a progressive neurological disorder that destroys muscular control, afflicts 1 percent of all Americans over age 55. It is marked by abnormally slow movement, uncontrollable tremors, stooped posture and a shuffling gait. "Given a very long life, most people would suffer some effects of the brain's naturally decreasing production of dopamine," Dr. Schneider explained. "Unfortunately, Parkinson's causes a loss of dopamine-producing cells above and beyond that seen in normal aging, and it accelerates the consequences of having too little dopamine in the brain." Doctors currently treat most Parkinson's patients with L-dopa, which acts as a replacement for their own dopamine. "While L-dopa ameliorates the symptoms, it loses its efficacy within a few years, often causes undesirable side effects, and does not deal with the underlying loss of dopamine-producing neurons," Dr. Schneider noted. Given that GM1 fosters repair and revitalization of remaining neurons, but does not create new neurons, it may prove most effective in early stages of the disease, he said. "However, since laboratory research suggests that only a small portion of the dopamine system needs to be spared or functionally recovered to achieve normal motor and cognitive skills, GM1 could benefit even patients with more established Parkinson's disease -- providing there are enough dopamine neurons remaining for GM1 to act on," Dr. Schneider suggested. The Neurology report involved 10 patients with mild to severe symptoms of the disease, most of whom had been taking L-dopa. At the outset, the patients were given a battery of tests to assess their functional abilities; those tests were repeated four times over an 18-week period. Each patient received a large intravenous dose of GM1 at the trial's beginning, then self-administered 200 mg of the drug each day by injection. Eight patients completed the full 18-week treatment; two patients dropped out early, feeling they were not benefitting from the trial. Among those eight participants, significant improvements in motor skills and ability to perform activities-of-daily-living occurred in the first eight weeks of the trial and stabilized over the remaining 10 weeks. "While the results of this initial study are encouraging, we must be careful not to overstate the significance of these findings," Dr. Schneider observed. "Since the patients in this study all knew they were receiving a new drug, their function may have improved due to psychological factors unrelated to the medication. Yet, since some patients have maintained their original improvement over almost two years now, it is hard to argue these effects are due primarily to psychological factors." The current clinical trial is a double blind, placebo controlled study of 50 patients. If that trial also demonstrates safety and effectiveness in GM1 treatment, the next step would be a multicenter trial that could begin as early as 1996. The big question Dr. Schneider and his colleagues will ultimately try to answer as their research progresses is whether early enough treatment with GM1 or related drugs could alter the course of the underlying disease. GM1 ganglioside is a normal constituent of nerve cell membranes and is known to moderate a number of neuron surface and receptor activities. The type of GM1 used in this study was extracted from cow brain. Dr. Schneider is also studying a semi-synthetic derivative of GM1, called LIGA 20, which could prove even more effective in restoring the function of the dopamine system. The MCPHU research was funded by the F.M. Kirby Foundation, the Marion and Joseph Wesley Foundation, the Alzheimer's Disease Research Center at Hahnemann, and through donations to the Parkinson's Disease Research Fund at Hahnemann. Dr. Schneider's co-authors of the Neurology report were MCPHU colleagues David Rothblat, Ph.D., Jillian Chapas-Crilly, B.S., and Louisa Seraydarian, Ph.D.; David Roeltgen, M.D., of The Health Education and Research Foundation of Williamsport (Pa.) Hospital, and Jayaraman Rao, M.D., of Louisiana State University Medical Center. -------------------------- End of Press Release -------------------- The following are other abstracts on the previous hypothsis and usages of GM1. <1> Authors Schneider JS. Yuwiler A. Institution Department of Neurology, Hahnemann University School of Medicine, Philadelphia, Pennsylvania 19102. Title GM1 ganglioside treatment promotes recovery of striatal dopamine concentrations in the mouse model of MPTP-induced parkinsonism. Source Experimental Neurology. 105(2):177-83, 1989 Aug. Abstract GM1 ganglioside (GM1) has in the past been reported to promote regenerative sprouting and functional recovery in both central and peripheral nervous systems. The present experiments were performed in order to investigate whether GM1 might have any therapeutic effect on young mice who had been exposed to the Parkinson-producing neurotoxin MPTP. GM1 caused moderate to dramatic increases in striatal dopamine levels, depending upon duration of exposure to GM1, in animals previously exposed to MPTP. Furthermore, the effects of GM1 on enhancing striatal dopamine levels were apparent when GM1 administration was delayed until 3 days after the last MPTP injection was given and these effects were not reversed when GM1 was withdrawn. Tyrosine hydroxylase (TH) immunohistochemistry of the striatum demonstrated increased numbers of TH-positive fibers and TH-positive terminal fields in GM1-treated animals as compared to animals that received only MPTP. TH immunohistochemistry of the substantia nigra revealed little or no loss of parts compacta neurons in the MPTP-treated mice. On the basis of these observations, GM1 appears to increase the dopamine content of the striatum by promoting or stimulating regenerative sprouting of dopaminergic terminals and perhaps collateral sprouting from remaining intact fibers in the MPTP model of Parkinsonism in the young mouse. We suggest that GM1 ganglioside may hold some promise as a potential adjunct in the treatment of Parkinson's Disease. <2> Authors Chapman J. Sela BA. Wertman E. Michaelson DM. Institution Department of Biochemistry, Faculty of Life Sciences, Tel-Aviv University, Ramat, Israel. Title Antibodies to ganglioside GM1 in patients with Alzheimer's disease. Source Neuroscience Letters. 86(2):235-40, 1988 Mar 31. Abstract Gangliosides are thought to have a role in neuronal development and regeneration while anti-ganglioside antibodies have been shown to impair these processes. In the present work we examined whether the neuronal degeneration in Alzheimer's disease is associated with the presence of anti-ganglioside antibodies. A significant level of antibodies specific to ganglioside GM1 but not to other gangliosides (GD1a, GD1b, GT1b and GQ1b) was found in patients with Alzheimer's disease as compared to normal age matched controls. A high level of antibodies to GM1 was also found in patients with multi-infarct dementia and Parkinson's disease with dementia but not in non-demented patients with other neurodegenerative diseases. These results may reflect a specific change in ganglioside metabolism which is associated with the neurodegenerative processes underlying Alzheimer's disease and other causes of dementia. <3> Authors Agnati LF. Fuxe K. Calza L. Goldstein M. Toffano G. Giardino L. Zoli M. Title Further studies on the effects of the GM1 ganglioside on the degenerative and regenerative features of mesostriatal dopamine neurons. Source Acta Physiologica Scandinavica. Supplementum. 532:37-44, 1984. Abstract By means of computer assisted morphometry and microdensitometry the effects of chronic GM-1 ganglioside treatment have been further evaluated on the degenerative and regenerative features of mesostriatal DA neurons in the rat brain. In this study mainly a rostrocaudal morphometrical analysis was performed in the substantia nigra of the lesioned side. The specificity of the action of the GM-1 ganglioside on the substantia nigra DA cells was evaluated by a comparison with antiinflammatory drugs such as betametazon and acetylsalicylic acid. In the rostrocaudal analysis it was demonstrated that chronic GM-1 treatment preferentially protected the caudally located dopamine nerve cells from degeneration after partial hemitransection, while instead this chronic GM-1 treatment increased tyrosine hydroxylase immunoreactivity mainly within the rostrally located DA nerve cells present close to the site of the lesion. Furthermore, the specificity of the GM-1 action was demonstrated by the absence of protective effects of chronic treatment with betametazon and acetylsalicylic acid on the dopamine nerve cells of the lesioned side. These results open up the possibility that chronic GM-1 treatment, by exerting a stimulatory metabolic action on the DA nerve cells located close to the lesion, can enhance the production of neurotrophic factors in these cells, which in turn can diffuse out to increase the survival of the less severely lesioned DA nerve cells located in the caudal part of the substantia nigra. These results indicate that chronic GM-1 treatment may be beneficial in the treatment of neurons undergoing degeneration, which takes place e.g. in Parkinson's disease and after mechanical injury to the brain due to accidents or neurosurgical operations. John Cottingham [log in to unmask] OR [log in to unmask]