Date: Wed, 2 Nov 94 16:25:55 EST From: Bob Broedel To: Stuart.Neilson@brunel.ac.uk Subject: Re: ALS Interest Group List =============================================================== == == == ----------- ALS Interest Group ----------- == == ALS Digest (#129, 27 September 1994) == == == == ------ Amyotrophic Lateral Sclerosis (ALS) == == ------ Motor Neurone Disease (MND) == == ------ Lou Gehrig's disease == == ----- == == This e-mail list has been set up to serve the world-wide == == ALS community. That is, ALS patients, ALS researchers, == == ALS support/discussion groups, ALS clinics, etc. Others == == are welcome (and invited) to join. The ALS Digest is == == published (approximately) weekly. Currently there are == == 350+ subscribers. == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == Sorry, but this is *not* a LISTSERV setup. == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. Access to ALS Sources? 2 .. Augmentative Communication 3 .. Deprenyl/Eldepryl/Selegiline 4 .. selegiline & ALS (1) ===== Access to ALS Sources? ========== Date : Mon, 26 Sep 1994 12:46:22 EST5EDT Sender : Neuroscience Information Forum : >From : "Dr. Al Roberts" Subject: Access to ALS Sources? I am searching for archival sources (e.g., case studies) that document progressions of persons with Amyotrophic Lateral Sclerosis [ALS]. I am particularly interested in those sources that provide neuroimaging data: PET, TCD, functional MRI. A 56-yr old ALS person has approached me and expressed interest/willingness to serve in the TCD-cognition research program I am pursuing. I want to better educate myself about ALS so as to maximize the participation of this person. (2) ===== Augmentative Communication ========== Date : 26 Sep 94 18:24:50 EDT >From : Greg Trautman <72262.1664@compuserve.com> Subject: Augmentative Communication Bob, Thanks for your continued work in publishing the ALS Digest. I have several things to share with the ALS Digest subscribers. A friend of mine has a Zygo MaCaw she would like to sell. This augmentative communication device is shaped like a keyboard and when one of its flat screen type keys is depressed a message you can prerecord is played. I think you can get up to 64 messages recorded on this device. Those people who use a Words+ type keyboard emulator to communicate may be interested in a relatively easy way to use computer hardware to get around the 640k conventional memory barrier. As you may or may not know some keyboard emulator programs which are terminate and stay resident programs take up a big chunk of conventional memory. Some commercial software programs like Compuserve's Doscim, WordPerfect 5.0, and Crosstalk Communicator run fine with the emulator programs, some like MS-Money, Quicken, Prodigy, Lotus 123, Windows, and lots of games don't have enough conventional memory space left to run in. However, it is possible to link two computers via a device called a TTAM in such a way to overcome this problem. Basicly one computer running the emulator program acts as a keyboard controlling the application software running on the other computer. Old ($200) 286 computers work fine for this. This type of setup allows the individual severely affected with ALS to correspond with family and friends all over the world directly via online email, or faxes. Also, in some areas of the country MS-Money can be linked with your bank so you can control your bank accounts directly. In addition it greatly increases the variety of conventional software applications you can take advantage of. Last but not least, I would like to know if there is a Internet USENET Newsgroup that deals specificly with ALS or augmentative communications devices. To the best of my knowledge there is not. Is there anything that any of us as subscribers to the ALS Digest can do to start such a newsgroup? It seems to me that a ALS related Internet newsgroup might get to more people (worldwide) than the ALS Digest whose subscription is sort of limited to word of mouth. Of course I would like to see the ALS Digest posted to such a Newsgroup. (To access CompuServe's Internet services, GO INTERNET. To access the USENET Newsgroups directly, a part of CompuServe's extended services, GO USENET.) If any of these comments pique you interest please contact me. Bob, thanks again for your good work, Greg Trautman E-mail Compuserve: 72262,1664 Internet: 72262.1664@compuserve.com Voice: (907) 276-7801 (3) ===== Deprenyl/Eldepryl/Selegiline ========== In ALS Digest #123 (06 September 1994) there was an article posted by Kathy Goeddel that was from the Prodigy BBS. The note was titled "Prodigy Medical Support Bulletin Board Survey on Neurontin". The survey mentioned that some of the ALS patients were taking the drug Eldepryl. Because of that, I thought the following note from the Parkinson's Disease list would be of interest here. rgds,bro ------------------------------------------------------------------- Date : Mon, 26 Sep 1994 11:09:56 -0500 Sender : Parkinson's Disease - Information Exchange Network : >From : "J. Philip Miller" Subject: Deprenyl - A Parkinson's Drug - 1994 Update -------------------------------------------------------------------- from another list........ -phil Forwarded message: Date : Sat, 24 Sep 94 16:22:00 MST >From : mednews@stat.com (HICNet Medical News) Subject: Deprenyl - A Parkinson's Drug - 1994 Update -------------------------------------------------------------------- Deprenyl - A 1994 Update The American Parkinson Disease Association Summer 1994 Newsletter Copyright 1994, Reproduced with Permission EDITOR'S NOTE: In 1989 APDA published "Deprenyl Update" an educational supplement authored by A. Lieberman, M.D., Chairman of the APDA Medical Advisory Board. At that time Deprenyl had just been approved by the FDA for use in this country. A short time ago an article on Selegiline (Eldepryl-Deprenyl) authored by E. Brunt, M.D., appeared in Parkinson Magazine highlighting the presentations made at a June 1993 neurologists meeting in Budapest, the city where Prof. Knoll developed this drug 30 years earlier. APDA is grateful to both Dr. Brunt and to Parkinson Magazine for sharing this article with our readers. Originally developed as a "psychic energizer" selegiline, also known as I-deprenyl or Eldepryl, appeared to be an irreversible inhibitor of the MAO-B enzyme. The MAO-B enzyme constitutes the main degrading pathway for dopamine, the transmitter which is deficient in the brain in Parkinson's disease (PD). An important advantage of selegiline compared with other MAO inhibitors was its lack of the "cheese effect". This effect is caused by the uptake of a food constituent, tyramine, which is present in high concentrations in cheese and Chianti wine, and causes the sudden, marked elevation of blood pressure in patients treated with other, previously used MAO inhibitors. In the seventies, Prof. Birkmayer, Prof. Csanda and Dr. Lees were among the first to apply, in the medical treatment of PD patients, the concept of slowing down the dopamine degradation by selegiline. The addition of selegiline to levodopa therapy appeared to be successful, as patients with motor fluctuations showed improvement and levodopa dosage could be reduced. In 1985 Birkmayer reported a nine year retrospective study from which appeared that addition of selegiline to levodopa therapy in PD patients also lengthened their lifetime. Thus, selegiline not only improved the response to levodopa, but also appeared to have a protective action against deterioration in PD. Support for a possible protective role of selegiline came from studies on two animal models of PD. In the "MPTP model" and the "6- hydroxy-dopa model", simultaneous administration of selegiline appeared to prevent the development of parkinsonism. The MPTP animal model of PD originates from the discovery that this substance, methylphenytetrahydropyridine was responsible for the development of a PD-like disease in users of a synthetic heroine-like drug in California in the early eighties. MPTP was found to be oxidized in the brain by the MAO-B enzyme into MPP+, which could destroy dopamine producing cells after being taken up into these cells, causing a PD-like syndrome. In this model, blocking of MAO-B enzyme prevents death of dopaminergic cells by MPTP. In the 6-hydroxy-dopa model of PD, this substance is injected into the brain of rodents in the tract formed by the dopamine nerve cell fibers running from the brainstem to their target in the basal ganglia. After being taken up into the nerve endings, 6-hydroxy-dopa also causes death of these cells, again producing a PD-like syndrome. Also in this model, selegiline prevents the damage, by blocking the uptake of the substance into the nerve cells. Thus in the second half of the previous decade, both human and animal studies suggested a possible neuroprotective action of selegiline in PD. To evaluate the results of previous open studies and to investigate the supposed neuroprotective effect of selegiline, several controlled studies have been performed by the groups of Dr. Langston, the Parkinson Study Group in the United States, and by the groups of Dr. Myllyla in Finland and Dr. Allain in France. The largest and most important of these studies was a multicenter study called "DATATOP" (deprenyl and tocopherol antioxidant therapy of Parkinson). Over 800 newly diagnosed PD patients from 40 centers in the US and Canada were included in this study and randomized to treatment with selegiline, vitamin E (tocopherol) or placebo. This study showed a strongly significant delay of the need to add levodopa therapy in the selegiline treated group. However, the interpretation as to whether this effect was due to a symptom- atic or protective effect remained controversial. In other words it could not be ascertained whether the delay was due to improvement of PD symptoms, or to slowing down of the progression of the disease. Critics argued that the one-month "wash-out" period following the withdrawal of selegiline, after which the groups of patients had been compared, was too short. Indeed, early this year, it was reported that the difference in favor of the selegiline treated group was no longer obvious after a prolonged wash-out period of 3 months. As the time needed for the restoration of MAO-B in humans is now estimated to be about 40 days, the current interpretation of the DATATOP study is that selegiline does have a symptomatic effect, and possibly a protective effect. A comparable conclusion on the action of selegiline was drawn by Dr. Myllyla in Finland from the interim analysis of a recently concluded study on the effect of selegiline in newly treated PD patients. Also in this study, the group treated with selegiline required introduction of levodopa at a later date. In addition, in the following years patients in the selegiline treated group needed less levodopa than those in the placebo treated group. In a recent report on the French selegiline multicenter trial, Dr. Allain also reported both an improvement of symptoms and a delay in progression in the selegiline treated group. As mentioned before, selegiline not only is being used in many countries in the treatment of PD, but also has had a major impact upon the research on PD and other neurodegenerative diseases. The exciting story of selegiline includes study on the possible role of MAO-B enzyme in the pathogenesis of PD and evidence for protective or even rescue effect of the drug upon endangered and damaged nerve cells. Investigations on the MAO enzymes have made clear that the two different types, A and B. have their own distribution both outside and inside the human brain, - and act upon different substances. The wide differences found between individuals on the amounts of MAO-A and MAO-B present in skin and blood may be important in the study of diseases such as PD. Although preferably metabolized by MAO-B, dopamine is also degraded by MAO-A and auto-oxidation. In the brain about 60% of MAO is of B type and the amount of MAO-B increases after age 60. After its production and excretion from the nerve cell to act upon the receptors of other nerve cells, dopamine is re-uptaken and subsequently degraded. This degradation takes place mainly outside the nerve cells, possibly in the nearby support glial cells, which are known to contain the highest concentration of MAO-B enzyme. It appears that in the normal process of dopamine degradation by MAO enzymes, toxic compounds such as hydrogen peroxide are formed, which may react to form "free radicals". These "free radicals" are aggressive oxidative substances which can impair the energy production or damage the membrane of nerve cells, causing their death. At the Budapest meeting, Profs. Olanow, Jenner and Youdim presented data suggesting that in dopamine cells of PD patients the production of the oxidizing substances is increased, while at the same time the defense mechanisms against this "oxidative stress' is reduced. As selegiline reduces the turnover of dopamine by impeding its degradation and increases one of the defending enzymes, reduction of "oxidative stress" may be one way in which it may protect nerve cells. Evidence to support a protective role of selegiline was also provided by Prof. Knoll. He has found a reduction of age related changes in the dopamine nerve cells of the substantia nigra and increased longevity in rats treated with selegiline. Maybe the most exciting findings on the action of selegiline were discussed at this meeting by Prof. Tatton. Several experiments suggest an action of selegiline which differs from MAO-inhibition or protection from oxidative free radicals. The first example is the MPTP-mouse model in which low dose selegiline given following MPTP administration at a time when lethal damage to neurons has been completed, triples the number of surviving nerve cells. At this dosage selegiline causes less than 50% inhibition of the MAO-B enzyme, so this cannot explain the rescue. Another example is an experiment in which one facial nerve is cut in rats of two weeks of age. At this age the cells of the facial nerve are dependent on nurturing substances ('trophic" or "growth" factors) from the muscles with which they are connected. These trophic factors are transported via the nerve and cutting of the nerve normally results in death for most of the nerve cells. Selegiline given to these rats both in high and in low dosage, more than doubled the number of surviving cells, apparently providing a substitute for the trophic factors. The suggestion that selegiline provides a substitute for trophic factors is also supported by the observation that in cultures of brain cells, selegiline promotes the growth of these cells and increases the production of growth factors. These examples suggest that selegiline, used in low dosage, may have a "rescue" effect, comparable to the effect of trophic factors. Several of these neurotrophic factors have been identified and they play an important role both in the growth and in maintenance of nerve cells, and they have also been shown to be important in fetal cell transplantation. It can be concluded that selegiline has proven to be a fascinating drug for its use in the treatment of PD and for its inspiration of a vast area of research on neurodegeneration. Actions of selegiline at different dosages include; MAO-B inhibition, dopamine re-uptake inhibition, reinforcement of defense against "oxidative stress", and substitution for trophic factors. A symptomatic and levodopa sparing effect of selegiline in the treatment of PD patients has become evident, supporting its use in patients already treated with levodopa. A protective action in PD patients, by diminishing the rate of progression of the disease, awaits further clinical proof. Therefore, the decision to use selegiline as monotherapy in early stage PD and during its further course is currently based upon the suggestion of possible benefit rather than evidence. Its suggested rescue effect and substitution of trophic factors for nerve cells opens most exciting perspectives. Selegiline has now taken a place in the treatment of PD and experimental work has opened exciting perspectives. Whether these promises will become a reality for the patients depends on clinical results. In the end only these count. Much work needs to be done, but the hope for a better treatment of this disease is a good reason for doing it. -- J. Philip Miller, Professor, Division of Biostatistics, Box 8067 Washington University Medical School, St. Louis MO 63110 phil@wubios.WUstl.edu - (314) 362-3617 [362-2693(FAX)] (4) ===== selegiline & ALS ========== This was once a part of ALS Digest #114 (30 July 1994). Reprinted here because of its relevance to the previous note. =============================================== Title : An open-randomized clinical trial of selegiline in : amyotrophic lateral sclerosis. Author : Mazzini L; Testa D; Balzarini C; Mora G Source : Journal of Neurology 1994 Feb;241(4):223-7 Abstract : Based on the hypothesis that free radicals play a general role in the neurodegenerative process in motor neuron disease, we tested selegiline in a group of patients affected by amyotrophic lateral sclerosis (ALS) to examine whether it might modify the progression of the disease. Patients were admitted if they were 25-80 years old and had a confirmed diagnosis of ALS with symptoms lasting no longer than 24 months. Patients with familial ALS, pure progressive bulbar palsy, primary lateral sclerosis or progressive muscle atrophy were excluded; a total of 111 patients were recruited. Fifty-three patients were randomly assigned to receive the drug (selegiline 10 mg/day orally for 6 months) and the remaining 58 were considered ALS controls. Mortality was similar in the two groups (4 and 5 patients respectively), though the difference was not statistically significant. Among the survivors, mean MRC and Norris disability scores and forced vital capacity were fairly similar in the two groups at all times and no statistically significant difference between treated and untreated patients was found. The results did not change when the data were related to age, duration and characteristics of onset of the disease. The rate of progression was significantly more rapid in patients with bulbar symptoms in both groups. Our data do not show any significant effect of selegiline in modifying the progression of ALS. =============================================== == end of als 129 ==