PMID- 11464953
OWN - NLM
STAT- MEDLINE
DCOM- 20010816
LR  - 20220309
IS  - 1466-0822 (Print)
IS  - 1466-0822 (Linking)
VI  - 1
IP  - 3
DP  - 2000 Jun
TI  - A phase I/II trial of recombinant methionyl human brain derived neurotrophic 
      factor administered by intrathecal infusion to patients with amyotrophic lateral 
      sclerosis.
PG  - 201-6
AB  - BACKGROUND: Brain derived neurotrophic factor (BDNF) is a potent survival factor 
      for motoneurons. This study investigated the safety and tolerability of 
      recombinant methionyl human BDNF (r-metHuBDNF) infused intrathecally by means of 
      an implanted pump in patients with ALS. METHODS: Twenty-five patients with 
      probable or definite ALS were treated with either r-metHuBDNF (25, 60, 150, 400 
      or 1000 microg/day) or placebo in a 12-week, randomized, double-blinded, 
      sequential, dose-escalation study. Test treatment was interrupted by a washout 
      period from days 11 to 25 to allow the evaluation of laboratory safety measures. 
      In each dose cohort four patients received r-metHuBDNF and one received placebo. 
      On completion of the double-blind period of the study all patients continued to 
      receive r-metHuBDNF in an open-label extension for up to 60 weeks. Lumbar 
      cerebrospinal fluid (CSF) samples were taken periodically from all patients for 
      the measurement of r-metHuBDNF levels and in a minority of patients these were 
      supplemented by cistemal samples. RESULTS: Within days after the initiation of 
      infusion the majority of patients receiving r-metHuBDNF reported mild sensory 
      symptoms, including paraesthesias or a sense of warmth, which were usually 
      confined to the lower limbs and were frequently exacerbated by neck flexion. In 
      most instances these symptoms decreased or even disappeared over several weeks. 
      Sleep disturbance, dry mouth, agitation and other behavioural effects were 
      encountered at higher doses (>150 microg/day) and necessitated dose reductions. 
      The spinal CSF levels of r-metHuBDNF were directly related to dose, with a lumbar 
      to cervical ratio of approximately 4:1. CONCLUSIONS: The intrathecal delivery of 
      r-metHuBDNF in doses of up to 150 microg/day was well tolerated and appears 
      feasible. The reversible CNS effects with higher dose indicate that BDNF can be 
      delivered cranially against CSF flow. The small number of patients and the design 
      of the study did not permit conclusions to be drawn about the efficacy of the 
      treatment.
FAU - Ochs, G
AU  - Ochs G
AD  - Department of Neurology, Julius-Maximilians University, Wurzburg, Germany.
FAU - Penn, R D
AU  - Penn RD
FAU - York, M
AU  - York M
FAU - Giess, R
AU  - Giess R
FAU - Beck, M
AU  - Beck M
FAU - Tonn, J
AU  - Tonn J
FAU - Haigh, J
AU  - Haigh J
FAU - Malta, E
AU  - Malta E
FAU - Traub, M
AU  - Traub M
FAU - Sendtner, M
AU  - Sendtner M
FAU - Toyka, K V
AU  - Toyka KV
LA  - eng
PT  - Clinical Trial
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Amyotroph Lateral Scler Other Motor Neuron Disord
JT  - Amyotrophic lateral sclerosis and other motor neuron disorders : official 
      publication of the World Federation of Neurology, Research Group on Motor Neuron 
      Diseases
JID - 100964775
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Recombinant Proteins)
RN  - 0 (r-metHuBDNF protein, recombinant)
SB  - IM
CIN - Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):141. PMID: 
      11464948
MH  - Adult
MH  - Aged
MH  - Amyotrophic Lateral Sclerosis/*drug therapy
MH  - Brain-Derived Neurotrophic Factor/*administration & dosage/*adverse effects
MH  - Double-Blind Method
MH  - Humans
MH  - Injections, Spinal
MH  - Middle Aged
MH  - Paresthesia/chemically induced
MH  - Recombinant Proteins/*administration & dosage/*adverse effects
MH  - Sleep Wake Disorders/chemically induced
MH  - Smell/drug effects
MH  - Taste/drug effects
EDAT- 2001/07/24 10:00
MHDA- 2001/08/17 10:01
CRDT- 2001/07/24 10:00
PHST- 2001/07/24 10:00 [pubmed]
PHST- 2001/08/17 10:01 [medline]
PHST- 2001/07/24 10:00 [entrez]
AID - 10.1080/14660820050515197 [doi]
PST - ppublish
SO  - Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):201-6. doi: 
      10.1080/14660820050515197.