ALS:

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ALS The Adverse Effects of Riluzole
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Amyotrophic Lateral Sclerosis (ALS)

• ALS, commonly known as Lou Gehrigs Disease, is
  a neuromuscular degenerative disorder

• Survival 3-4 years after diagnosis

• No known cure, only symptomatic treatment is
  available

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Superoxide Dismutase (SOD)

• The accumulation of glutamate is believed to be
  involved in ALS

• Defective superoxide dismutase (SOD) is
  believed to act as a peroxidase that oxidizes
  lipids

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Treatment with Riluzole

• FDA
• Prior to FDA approval in 1995, Riluzole was made
  available to 3,000 patients through an early
  access program

• Riluzole, sold under the trade name Rilutek, is
  currently
• the only FDA-approved treatment for ALS

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• Biochemical
• Riluzole (2-amino-6-trigluoromethoxy
  benzothiazole) is a glutamate release inhibitor,
  possibly by blocking sodium channels

• Riluzole is thought to be moderately useful or,
  
• possibly, not useful at all

• Recognized side effects nausea, vomiting,
• increased asthenia (loss of strength), and
  increased
• spasticity (uncontrollable muscle contraction
  and
• movement)

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What is Methemoglobinemia?
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Methemoglobin

• Oxidation of the Fe (2) atom to Fe (3) in
  hemoglobin creates methemoglobin, which is unable
  to reversibly bind with O2

• In healthy people, methemoglobin is
• maintained at 1

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Methemeglobinemia

• Methemoglobinemia is a disorder where
  methemoglobin increases to much higher levels

• Ultimately, methemoglobinemia prevents
• adequate amounts of O2 from being delivered
  to
• body tissues

• Methemoglobinemia is treated with methylene
• blue, which inhibits oxidase activities

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A Case Study of anUnanticipated Riluzole Side
Effect
Methemoglobinemia
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Prior to Hospitalization

• 43-yr old ALS patient had been treated with
  Riluzole over the previous two years

• During this time patient suffered weight loss
  of 8
• kg (18 lbs), difficulty speaking, required
• assistance to walk, some difficulty
  swallowing,
• and depression

• Patient ingested 2800 mg of Riluzole (normal
  
• dosage is 100 mg/day)

• Patient hospitalized 6 hours after ingestion

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After Hospitalization

• Initial symptoms
• Cyanosis, 18.3 methemoglobin in blood
• No other significant symptoms were observed

• Day 1
• 50 g activated charcoal administered to reduce
  serum riluzole
• Methylene blue administered to counteract
  rapidly increasing methemoglobin in blood

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• Day 3
• Day 5
• Day 7

• Patient was put on a respirator

• Patient was weaned from respirator

• More aggressive treatment was withheld due to
  patients condition

• Patient dies of respiratory failure associated
  with ALS

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Physicians Conclusions
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• Clinical and laboratory studies indicated
• Patient did not suffer from any metabolic
  disorders
• no neutropenia (abnormally low levels of certain
  white blood cells)
• no infectious diseases
• no impairment of hepatic, renal or cardiac
  function
• no other toxins were present

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• Methemoglobinemia developed as a result of the
  high riluzole dose ingested

• Attending physician notified the
• pharmaceutical company of this case as
• evidence that Riluzole can cause
• methemoglobinemia

• As a result, methemoglobinemia has
• been included on the product labeling,
• with note that this is the only known case

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Implications
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• ALS is a devestating neurdegenerative disease
  with no known cure
• Riluzole, the only approved treatment, likely
  caused methemoglobinemia in a patient
• Reaction to a drug in excess is important
  information- Why was there no previous knowledge?
• Riluzole is also prescribed for many other
  diseases
• Does it pose a risk for those patients?
• Should the FDA take action or require more
  testing?

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Acknowledgements
Group Members

• Roger Rothschild, Project Manager
• Amy Tidwell, Creater
• Katie Schaetzle, Presenter
• Danielle Arnold, Reviewer
• Dr. Drew, Reference
• Dr. Clausen, Reference

Additional Help
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References

• R.D. Azbill, X. Mu, J.E. Springer, Riluzole
  increases high-affinity glutamate uptake in rat
  spinal cord synaptosomes, Brain Research 871
  (2000) 175-180.
• B.D. Kretschmer, Ulrich Kratzer, Werner
  J.Schmidt, Riluzole, a glutamate release
  inhibitor and motor behavior, Naunyn-Schmiedeberg
  s Archives of Pharmacology vol. 358 issue 2
  (1998) pp 181-190.
• D. Voet, J.G. Voet, C.W. Pratt, Fundamentals of
  Biochemistry. New York John Wiley and Sons,
  1999.
• A. Viallon, Y. Page, J. C. Bertrand,
  Methemoglobinemia Due to Riluzole, New England
  Journal of Medicine vol. 383 no. 9 (2000)
  665-666.
• FDA News release, FDA Approves First Drug for Lou
  Gehrigs Disease 12/12/1995.