=============================================================== == == == ----------- ALS INTEREST GROUP ----------- == == ALS Digest (#55, 15 AUGUST 1993) == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == == == All interested people may "broadcast" messages to == == ALS Digest subscribers by sending to: == == als@huey.met.fsu.edu == == == =============================================================== (1) ===== why? ========== > >Date: 11 Aug 93 18:55:54 EDT >From: RON LEEB <72613.2113@CompuServe.COM> >Subject: Re: +Postage Due+als 53 (MNTF) > >Thank you Bob for the ALS Digest. How did you come to form >it and what is your field of study--Ronn. > My wife has ALS. I tried to locate an on-line discussion but could not find one ... so I started this one. My field of study is computer networking. I do not have a background in neurology, but am working hard to get those kinds of folks on-line with us here. This net is not perfect, but it is much better than I ever thought it would be (and I am certain that it will get better!). -bro (2) ===== duplicate copies, etc. ========== > >Date: 11 Aug 93 23:39:27 EDT >From: Barry Goldberg <71154.330@CompuServe.COM> > >Bob, you asked us to let you know if we are receiving more that one >copy of each ALS Digest. I thought that this had cleared up but >apparently I am still receiving at least two copies...and, believe >it or not, sometimes three! Hope you can correct this particularly >since every message on INTERNET now seems to come to me postage due! >You're doing a terrific job! My only regret was reading in the last >issue the disturbing news about Regeneron's initial results on CNTF. >Keep plugging away on those databases! >With deepest appreciation, Barry. >--- MDA -- Working to find the cure for neuromuscular disease > Regarding duplicate copies ... the last time it happened was because one of our graduate students re-booted "huey" as though it were a single-user machine. He was sitting at the console and apparently thought he was sitting at a MSDOS machine that had locked up. The re-boot was done as an ALS Digest was being mailed to the list of 125+ subscribers. After the re-boot, the computer got confused and re-transmitted to the entire list. A few weeks ago things here got really bad, in that our network was hit by lightning ... (it happened while I was in Miami to take my wife to a CNTF trail session) but hopefully things are OK with the equipment now. That "postage due" thing is (I think) something that happens only on CompuServe, I have not heard of that happening on MCI Mail, Delphi, Genie, AmericaOnLine, etc. It is nothing that can be controlled from my end. Maybe you should move to a different system? Regarding the CNTF Phase II trails. As I understand the situation, the Phase II trials were done on 40 patients and the dosage was minimal, to see if the CNTF was "safe" to use. The Phase III trials are being done with a larger group, with two higher dosage levels, to see if it actually works. Fact is, the CNTF clinical trial team is a very tight-lipped group ... it is hard to tell what is happening with Phase III. -bro (3) ===== re: MNTF ========== Date : Thu, 12 Aug 93 00:52:01 -0400 Sender : pathology@a1.mscf.upenn.edu >From : "PATHOLOGY & LAB. MEDICINE" Subject: RE: als 53 (MNTF) Bob, the motorneuron trophic factor may go under a different name. Here are several articles that you might want to take a look at. The pair from Nature in 1992 might be particularly relevant. Gregg Wells Division of Neuropathology Department of Pathology University of Pennsylvania Philadelphia, PA Email: pathology@a1.mscf.upenn.edu MEDA (NLM)92350295. ID (NLM)92350295. AU Oppenheim R W. TI Motor neuron diseases. High hopes of a trophic factor . SO Nature. 1992 Aug 6; 358(6386): 451-2. CM Comment on:'Nature'1992 Aug 6;358(6386):502-4. MJ Motor Neuron Disease--metabolism--ME--MJ. Nerve Growth Factors--physiology--PH--MJ. Nerve Tissue Proteins--physiology--PH--MJ. CT Animal. Human. Mice. RN 0 (neurotrophic protein). 0 (Nerve Growth Factors). 0 (Nerve Tissue Proteins). PT COMMENT. NEWS. IS 0028-0836 MEDA (NLM)93213496. ID (NLM)93213496. AU Hughes R A.; Sendtner M.; Goldfarb M.; Lindholm D.; Thoenen H. IN Department of Neurochemistry, Max-Planck-Institute for Psychiatry, Planegg-Martinsried, Germany. TI Evidence that fibroblast growth factor 5 is a major muscle-derived survival factor for cultured spinal motoneurons. SO Neuron. 1993 Mar; 10(3): 369-77. AB We examined the potential role of fibroblast growth factor 5 (FGF-5) as a target-derived trophic factor for spinal motoneurons. Northern analysis of total RNA from rat skeletal muscle revealed an FGF-5 mRNA transcript both during the period of embryonic motoneuron death and in the adult. Recombinant human FGF-5 supported the survival of highly enriched cultures of embryonic chick motoneurons. Significant proportions of the motoneuron survival activity of rat skeletal muscle extracts could be immunoprecipitated using an antiserum to FGF-5. The immunoprecipitable activity was present in soluble and matrix-bound forms in embryonic muscle, but bound exclusively to the extracellular matrix in adult muscle. These results, along with the secretory nature of FGF-5, suggest that FGF-5 may act as a target-derived trophic factor for motoneurons. Author. MJ Fibroblast Growth Factor--physiology--PH--MJ. Motor Neurons--physiology--PH--MJ. Muscles--metabolism--ME--MJ. Spinal Cord--cytology--CY--MJ. MN Aging--metabolism--ME. Cell Survival. Cells, Cultured. Fibroblast Growth Factor--genetics--GE. Muscles--embryology--EM. Precipitin Tests. RNA, Messenger--metabolism--ME. CT Animal. Chick Embryo. Support, Non-U.S. Gov't. RN 0 (RNA, Messenger). 129653-64-1 (fibroblast growth factor-5). 62031-54-3 (Fibroblast Growth Factor). PT JOURNAL ARTICLE. IS 0896-6273 MEDA (NLM)93213495. ID (NLM)93213495. AU Koliatsos V E.; Clatterbuck R E.; Winslow J W.; Cayouette M H.; Price D L. IN Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196. TI Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. SO Neuron. 1993 Mar; 10(3): 359-67. AB The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) act upon populations of neurons that express specific receptors. The present study demonstrates that BDNF rescues motor neurons from degeneration and may also play a role in the normal physiology of these cells. BDNF is expressed in the local environment and in muscle targets of motor neurons; muscle expression is up-regulated by denervation. The alpha motor neurons express the gene encoding p145trkB, a receptor involved in BDNF signal transduction, whereas a subset of motor neurons express p75NGFR. BDNF is transported selectively to alpha motor neurons from skeletal muscles. Finally, BDNF prevents motor neuron death in the axotomized facial nucleus of the neonatal rat. The effects of BDNF on motor neurons raise the possibility that some neurotrophins may be useful in treating patients with motor neuropathies and amyotrophic lateral sclerosis. Author. MJ Motor Neurons--physiology--PH--MJ. Nerve Growth Factors--physiology--PH--MJ. Nerve Tissue Proteins--physiology--PH--MJ. MN Biological Transport. Muscles--metabolism--ME. Nerve Degeneration. Nerve Growth Factors--metabolism--ME. Rats, Sprague-Dawley. Receptors, Endogenous Substances--classification--CL. Receptors, Endogenous Substances--metabolism--ME. Recombinant Proteins. Spinal Cord--metabolism--ME. CT Animal. Rats. Support, Non-U.S. Gov't. Support, U.S. Gov't, P.H.S. RN 0 (neurotrophic protein). 0 (neurotrophin 3). 0 (Nerve Growth Factors). 0 (Nerve Tissue Proteins). 0 (Receptors, Endogenous Substances). 0 (Recombinant Proteins). PT JOURNAL ARTICLE. IS 0896-6273 MEDA (NLM)92350301. ID (NLM)92350301. AU Sendtner M.; Schmalbruch H.; Stockli K A.; Carroll P.; Kreutzberg G W.; Thoenen H. IN Department of Neurochemistry, Max-Planck-Institute for Psychiatry, Martinsried, Germany. TI Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy . SO Nature. 1992 Aug 6; 358(6386): 502-4. CM Comment in:'Nature'1992 Aug 6;358(6386):451-2. AB Ciliary neurotrophic factor (CNTF) supports the survival of embryonic motor neurons in vitro and in vivo, and prevents lesion-mediated degeneration of rat motor neurons during early post-natal stages. Here we report that CNTF greatly reduces all the functional and morphological changes in pmn/pmn mice, an autosomal recessive mutant leading to progressive caudo-cranial motor neuron degeneration. The first manifestations of progressive motor neuronopathy in homozygous pmn/pmn mice become apparent in the hind limbs at the end of the third post-natal week, and all the mice die up to 6 or 7 weeks after birth from respiratory paralysis. Treatment with CNTF prolongs survival and greatly improves motor function of these mice. Moreover, morphological manifestations, such as loss of motor axons in the phrenic nerve and degeneration of facial motor neurons, were greatly reduced by CNTF, although the treatment did not start until the first symptoms of the disease had already become apparent and substantial degenerative changes were already present. The protective and restorative effects of CNTF in this mouse mutant give new perspectives for the treatment of human degenerative motor neuron diseases with CNTF. Author. MJ Motor Neuron Disease--drug therapy--DT--MJ. Nerve Tissue Proteins--therapeutic use--TU--MJ. MN Cell Count. Cell Line. Gene Therapy. Mice, Neurologic Mutants. Motor Neuron Disease--pathology--PA. Motor Neurons--pathology--PA. Nerve Tissue Proteins--genetics--GE. Phrenic Nerve--pathology--PA. Pons--pathology--PA. Transfection. CT Animal. Mice. Support, Non-U.S. Gov't. RN 0 (neurotrophic protein). 0 (Nerve Tissue Proteins). PT JOURNAL ARTICLE. IS 0028-0836 (4) ===== nitro ========== APn 08/11 1300 Brain Protector By MALCOLM RITTER AP Science Writer NEW YORK (AP) -- The common heart drug nitroglycerin may be useful someday in treating brain damage from stroke, dementia from AIDS and some other brain conditions, a test-tube study suggests. Researchers found evidence that nitroglycerin and similarly acting drugs protect brain cells from a fatal over-stimulation that is thought to play a role in those conditions as well as Parkinson's, Huntington's and Lou Gehrig's diseases. ~~~~~~~~~~~~~~~~~~~~~ Animal studies also have shown evidence of a possible usefulness in stroke and AIDS dementia, said neurologist Dr. Stuart Lipton of Harvard Medical School and Children's Hospital in Boston. But he said people should not take nitroglycerin for the brain conditions yet, because scientists have not yet found the proper dose to avoid a potentially serious drop in blood pressure. Nitroglycerin is normally used to treat a painful heart condition called angina pectoris. Lipton and co-authors present the test-tube work in Thursday's issue of the journal Nature. They focused on a substance in the body called nitrogen monoxide. They found evidence that one form, called nitric oxide, can lead to death of brain cells, while another form, nitrosonium ion, protects brain cells. Either form can switch to the other under the proper chemical conditions, researchers said. Further study may provide a way to harness the protective form while suppressing the harmful one, they said. Nitroglycerin acts like the beneficial form, Lipton said in a telephone interview. It affects a protein structure on brain cells called the NMDA receptor, which receives chemical messages from neighboring brain cells. Lethal over-stimulation of the NMDA receptor is implicated in damage from stroke and the other brain conditions, researchers said. Nitroglycerin molecules appear to prevent over-stimulation by attaching part of themselves to the NMDA receptor, Lipton said. Dr. Solomon Snyder of Johns Hopkins University School of Medicine said the idea of using nitroglycerin for the brain conditions is "very interesting," but that it would be tricky because of the blood pressure problem. (5) ===== American Biogenetic Sciences ========== OTC 08/12 1126 American Biogenetic Sciences collaborates with ... BERLIN (AUG. 12) BUSINESS WIRE - Professor Heinz Nau at the Free University of Berlin announces Thursday a five year collaboration agreement with American Biogenetic Sciences Inc. (NASDAQ:MABXA) (ABS) to develop new compounds as potential epilepsy and neuroprotective therapeutics. Professor Nau, a world recognized neuropharmacologist, has developed a series of novel antiepileptic agents without the common side effects associated with the use of present anticonvulsants. These side effects include sedation and birth defects in infants exposed during pregnancy. Professor Nau uses computer-modelling technology to establish structure-activity relationships necessary to develop safe, potent and efficacious agents. In addition, Professor Nau has made a related series of compounds which, in collaboration with Dr. Ciaran Regan at University College Dublin, Ireland have been demonstrated to have a marked nerve cell regenerative potential. Dr. Regan's laboratory is funded by ABS under their Alzheimer program. These compounds will be investigated as potential treatments for other neurodegenerative disorders which may include Alzheimer's disease, Parkinson's disease, Lou Gehrig disease and others. ~~~~~~~~~~~~~~~~~~ American Biogenetic Sciences Inc., is a biopharmaceutical company which conducts research to develop and commercialize monoclonal antibody based products for the diagnosis and treatment of cardiovascular disease, cancer, Alzheimer's disease and other neurological disorders. ABS has also developed a recombinant vaccine for Hepatitis A virus and other infectious diseases. The company has research centers in the U.S., Europe, Russia and Japan. CONTACT: American Biogenetic Sciences Inc. 1375 Akron Street Copiague, NY 11726 TEL 516-789-2600 FAX 516-841-5328 ATTN: Fran Giambanco or Leonard Suroff (6) ===== ethics ========== Date : Thu, 5 Aug 1993 11:49:06 EDT Sender : BIOMED-L Biomedical Ethics >From : medethx Subject: International Directory of Bioethics Organizations A new INTERNATIONAL DIRECTORY OF BIOETHICS ORGANIZATIONS has just been published by the National Reference Center for Bioethics Literature at the Kennedy Institute of Ethics, Georgetown University. This work identifies 278 organizations throughout the world which are engaged in the study, teaching, research or practice of bioethics or health care ethics in general. It is arranged alphabetically by country, by state within the United States, and then by the name of each organization. Different indexes supply names of organizations granting academic degrees, those providing consulting services, and others that have an international focus. Prices, including shipping charges, are: $35 in North America $40 outside North America, surface mail $55 outside North America, airmail printed matter Prepayment in US dollars is required. To order, send a check made payable to the Kennedy Institute of Ethics, or charge to ____MasterCard or ____Visa, with the information below. Charge Account Number:_____________________________________________________ Authorized signature:______________________________________________________ Name as it appears on the card:____________________________________________ Ship to: Name:______________________________________________________________________ Address:___________________________________________________________________ City,State,Zip/Postal Code:________________________________________________ Country:___________________________________________________________________ Telephone:_________________________________________________________________ Mail order to: National Reference Center for Bioethics Literature Kennedy Institute of Ethics Georgetown University Washington, DC 20057-1065 USA FAX: 1-202-687-6770 E-Mail: medethx@guvm.bitnet medethx@guvm.ccf.georgetown.edu For more information call 1-800-MED-ETHX (US and Canada) or 1-202-687-3885. (7) ===== FDA process ========== I have included the following note because it serves as an example that illustrates how long it takes to get new drugs approved by the FDA. ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: Food & Drug Administration News ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: Licensing of Interferon beta-1b for treatment of Multiple Sclerosis P93-31 Food and Drug Administration FOR IMMEDIATE RELEASE Monica Revelle (301) 443-4177 July 23, 1993 Home (410) 290-6575 The Food and Drug Administration today announced the licensing of Interferon beta-1b, the first product for the treatment of certain patients with multiple sclerosis and the first biotechnology product to be licensed under FDA's accelerated approval regulations. Multiple sclerosis is a chronic, often disabling disease of the central nervous system that occurs when a protective sheath surrounding the nerve fibers breaks down. Nearly 30 percent of multiple sclerosis patients suffer from a relapsing-remitting form of the disease in which symptoms disappear totally or partially after a flare-up and are followed by a period of stability that can last for months or years. A clinical trial involving 372 patients with relapsing-remitting multiple sclerosis indicated that administration of Interferon beta-1b by injection every other day decreased the frequency of flare-ups and kept more patients free of flare-ups over a two-year treatment period. "This product marks an important first," said FDA Commissioner David A. Kessler, M.D. "It's not a cure, but it will help relieve debilitating symptoms for many multiple sclerosis patients for whom no other relief is available. "We gave this drug a top-priority review," he said. "This demonstrates our commitment to act quickly to make drugs available to those who need them." The accelerated approval policy allows for expediting the approval of therapies that provide a meaningful therapeutic benefit for patients with serious illnesses. It enables FDA to approve therapies as soon as their safety and effectiveness can be reasonably established. Accelerated approval relies solely or in part on "surrogate endpoints" -- laboratory measurements or physical signs -- for evidence of effectiveness. The surrogate endpoints are believed to be likely to predict benefit for the patient. The surrogate endpoints used in licensing Interferon beta-1b were data from magnetic resonance imaging (MRI) scans of the brain, which supported the clinical findings. MRI scans indicated that after two years of treatment, there was a greater increase in the multiple sclerosis lesion areas in the brains of patients treated with a placebo than in patients treated with Interferon beta-1b. The trials did not demonstrate, however, that the findings on MRI scans correlate with slower disease progression. The accelerated approval regulations require the product's manufacturer, Chiron Corp. of Emeryville, Calif., to conduct postmarketing studies to investigate the effectiveness of Interferon beta-1b in slowing or preventing progression of multiple sclerosis. Adverse reactions following administration of Interferon beta-1b included inflammation and pain at the injection site and flu-like symptoms. The use of other types of interferon has also been associated with occasional serious side effects including abnormal liver function tests and severe depression, including suicidal depression. These events were also observed in multiple sclerosis patients taking Interferon beta-1b in clinical trials. An estimated 250,000 to 350,000 Americans are affected by multiple sclerosis, which affects twice as many women as men. Two thirds of the patients experience their first symptoms between the ages of 20 and 40. On March 19, the Peripheral and Central Nervous System Drugs Advisory Committee recommended approval of Interferon beta-1b for decreasing the frequency of flare-ups in patients with relapsing-remitting multiple sclerosis. On June 3, FDA sent an "approvable" letter that informed Chiron Corp. that the agency was prepared to approve the product when certain conditions were met. Chiron then submitted the requested information and made a commitment to conduct postmarketing studies. Interferon beta-1b is manufactured by Chiron under the trade name "Betaseron." Berlex Laboratories of Alameda, Calif., will distribute it. MILESTONES IN BETASERON APPROVAL PROCESS Betaseron was licensed under the accelerated approval policy. o Biologics licensed in the normal process take an average of 28 months for FDA review of the Product License Application (PLA). The FDA review of Betaseron, including intensive discussions and presentation of more data, took just 12 months. o Betaseron is the first biotechnology product licensed under the accelerated approval process. It was preceded by DDC, a drug for AIDS, which was approved under the same program last year. o The review of the PLA for Betaseron was the first collaborative effort on a marketing application by the Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research. IMPORTANT DATES March 3, 1983 Investigational New Drug Application filed Nov. 11, 1988 FDA designates Betaseron as an Orphan Drug July 23, 1992 Chiron Corp. files the PLA with FDA March 19, 1993 Peripheral and Central Nervous System Drugs Advisory Committee recommends approval May 30, 1993 FDA completes its review of the PLA June 3, 1993 FDA sends Chiron "Approvable Letter" July 23, 1993 FDA licenses Betaseron == end of als 55 ==