A Faulty Garburator and the Community Pharmacist

5/27/2015
A Faulty Garburator
and the Community Pharmacist
Blair Seifert, Pharm.D.
Clinical Pharmacy Coordinator – Pediatrics
Saskatoon Health Region
May 23, 2015
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Conflict of Interest
None
Declaration
• Former member of the Garrod Society. A
Canadian group of metabolic specialists that
reviews & prepares guidelines for the
management of select metabolic disorders.
• Brand names of some products may be used
for clarity; they do not represent promotion
of a product from any specific manufacturer
Learning Objectives
At the conclusion of this interactive session, the learner will:
1. Summarize the scope of inborn errors of metabolism in
pediatric and adult patients.
2. Describe the role of the lysosome in general and specifically in
select metabolic disorders.
3. Identify the scope of services required from the community or
hospital pharmacist in support of clients requiring enzyme
replacement therapy, including other medications and services
for their underlying condition.
4. Describe future roles for pharmacists in support of patients
with lysosomal storage disorders due to changes in screening,
early treatment and the changes in morbidity and mortality.
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OUTLINE
• Our biochemical factory
• Garburator
• LSD
• So what?
• The future is now?
Pharmacist Willard
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http://th06.deviantart.net/fs70/PRE/i/2010/020/5/a/Muscular_Body_by_AJG907.jpg
http://cache2.asset-cache.net/xc/469586421.jpg?v=2&c=IWSAsset&k=2&d=hDptCvDxsB5KhVuYpWBcDk9R95W8RY4N00YNFLhLcc0DPgx9zxX-29c9KL0EVAt0
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Our Biochemical
Factory
https://s-media-cache- ak0.pinimg.com/originals/ca/a8/2e/caa82e4d77912df4c1d093875e446356.jpg
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Our Biochemical
Factory
• Uses:
• Substrates (amino acids, carbohydrates, fats)
• Enzymes (proteins)
• Co-factors
(vitamins, trace minerals)
Our Biochemical
Factory
• Complex of chemical reactions
• Production of energy
• Growth & repair
• Waste removal
http://photos.gograph.com/thumbs/CSP/CSP962/k9626423.jpg
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THE HUMAN GARBURATOR
Garburator
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Lysosome
http://hyperphysics.phy-astr.gsu.edu/hbase/biology/imgbio/lysosome.gif
http://38ccda.medialib.glogster.com/media/54352ec72d32a8fa7e573e3853e559f4258348eadfd10c34dffb2e
bd1f873ec7/lysosome.jpg
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Lysosome
http://faculty.muhs.edu/klestinski/cellcity/lysosomedata_files/image001.jpg
Lysosome
http://www.sivabio.50webs.com/lyso004.jpg
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Lysosomes as catabolic centres of the cell.
Frances M. Platt et al. J Cell Biol 2012;199:723-734
http://jcb.rupress.org/content/199/5/723.figures-only
Lysosome
http://www.biology4kids.com/files/art/cell_lysosome2.png
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Lysosome
https://pbs.twimg.com/profile_images/3171562716/4131da13f5
20b5cabdb06a56239c08b8.jpeg
Sometimes Things Go Wrong
https://uwaterloo.ca/centre-for-teaching-excellence/sites/ca.centre-for-teaching-excellence/files/styles/sidebar-220pxhttp://s3.amazonaws.com/pbblogassets/uploads/2013/04/donkey-pulling-cart.jpg
wide/public/When%20Things%20Go%20Wrong%20Handling%20Problems%20Group.jpg
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METABOLIC
DISORDERS
http://www.epainassist.com/im
ages/metabolic-disorders.jpg
Metabolic Disorders
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Metabolic Disorders
Small Molecule Disease

Carbohydrate

Protein

Lipid

Nucleic Acids
Organelle Disease

Mitochondria

Peroxisomes

Cytoplasm

Lysosomes
http://www.nutrikalp.com/images/meta-bolic.jpg
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Lysosomal Storage Disorders
[LSD]
Every LSD results from a problem with the
lysosomal process by which enzymes rid
cells of substrate.
http://4.bp.blogspot.com/-m18GlXRavbM/TV7JL0yQYgI/AAAAAAAACd8/W_qQk8jDVY/s1600/lysosomal%2Bstorage%2Bdiseases.png
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HISTORY OF THE LSDs
Gaucher cell 1882
Ernest GAUCHER (1854-1919)
Pompe Disease
http://www.kwikwap.co.za/p4p/photos/Muscle.JPG
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Lysosomal Storage Diseases


Inherited disorders
Autosomal recessive
 rare 1:5,000 – 8,000
http://jcb.rupress.org/content/199
/5/723/F2.large.jpg
Lysosomal storage diseases are inborn errors of
metabolism, the hallmark of which is the accumulation, or
storage, of macromolecules in the late endocytic system.
They are monogenic disorders that occur at a collective
frequency of 1 in 5,000 live births and are caused by
inherited defects in genes that mainly encode lysosomal
proteins, most commonly lysosomal enzymes. A subgroup
of these diseases involves the lysosomal storage of
glycosphingolipids. Through our understanding of the
genetics, biochemistry and, more recently, cellular aspects
of sphingolipid storage disorders, we have gained insights
into fundamental aspects of cell biology that would
otherwise have remained opaque. In addition, study of these
disorders has led to significant progress in the development
of therapies, several of which are now in routine clinical use.
Emerging mechanistic links with more common diseases
suggest we need to rethink our current concept of disease
boundaries.
http://www.nature.com/nature/journal/v510/n7
503/full/nature13476.html
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Lysosomal Storage Diseases

Tay-Sachs (sphingolipidosis)
1/27 to 1/30 Ashkenazim Jews are carriers
also: Acadians, Cajuns

Sanfilippo Syndrome (MPS III)

most common MPS
1:70,000
Gaucher Disease (glucocerebroside)
prevalence 1:100,000 (Canada)
Ashkenazi Jewish population
(1 in 855 live births)
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LSD Sub-Categories
 glycosoaminoglycans
 glycan in glycoproteins
 glycogen
 sphingolipid
 polypeptides
 transport defects
glycosaminoglycans
" the mucopolysaccharidoses"
MPS I
(Hurler, Hurler-Scheie, Scheie)
MPS II
(Hunter)
MPS III
(San filipo Types A,B,C and D)
MPS IV
(Morquio type A and B)
MPS VI
(Maroteaux-Lamy)
MPS VII
(Sly)
MPS IX
(Hyaluronidase deficiency)
Multiple Sulfatase deficiency
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glycan portion of glycoproteins
Aspartylglucosaminuria
Fucosidosis, type I and II
Mannosidosis
Sialidosis, type I and II
glycogen
Pompe disease
sphingolipid
Acid sphingomyelinase deficiency
(Niemann-Pick A & B)
Fabry disease
Farber disease
Gaucher disease, type I, II and III
GM1 gangliosidosis, type I, II and III
GM2 gangliosidosis
(Tay-Sachs type I, II, III and Sandhoff
Krabbe disease
Metachromatic leukodystrophy, type I, II and III
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polypeptides
Pycnodysostosis
Defective degradation or transport of
cholesterol, cholesterol esters
or other complex lipids
Neuronal ceroid lipofuscinosis, type I, II, III and IV
[Batten Disease]
Multiple deficiencies of lysosomal enzymes
Galactosialidosis
Mucolipidosis, type II and III
Transport and trafficking defects
Cystinosis
Danon disease
Mucolipidosis type IV
Niemann-Pick type C
Infantile sialic acid storage disease
Salla disease
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https://igm.jhmi.edu/content/johns-hopkins-lysosomal-storage-disease-program
Phenotypic Variation
• Genotype
• is the genetic makeup of a cell, an
organism, or an individual usually with
reference to a specific characteristic
under consideration.
• Phenotype
• the composite of an organism's
observable characteristics or traits
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http://www.maroteaux-lamy.com/en/images/rapid_slow_intermediate_advancing-MPSVI-2.jpg
MPS 1 (Hurler Syndrome)
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https://igm.jhmi.edu/sites/default/files/lsd-program/Fig2_JohnsHopkinsLSDprogram.jpg
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Enzyme Replacement Therapy
• Not a foreign concept to pharmacists
e.g. pancrealipase (e.g. Creon, Cotazyme)
• In lysosomal storage disease:
•
•
•
•
Expensive
Primarily intravenous
“loss leaders” – big time!
or great opportunity
Enzyme Replacement Therapy
Disorder
Enzyme
Product
MPS I (Hurler)
Laronidase
Aldurazyme®
MPS II (Hunter)
Idursulfase
Elaprase®
MPS IVa (Morquio A)
Elosulfase
Vimizim
MPS VI (Maroteau-Lamy)
Galsulfase
Naglazyme®
Fabry’s disease
Agalsidase beta
Fabrazyme®
Replagel
Gaucher Type I & III
Imiglucerase
Cerezyme®
Glycogen Storage Disease
Type II (Pompe)
Alglucosidase alfa
Myozyme®
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Economic cost
ERT is current most effective treatment (non neurodegenerative LSDs):
Disease
Treatment
Annual Cost
(per patient in $)
Gaucher
ERT
145,000 - 290,000
Gaucher
SRT
91,000
Fabry
ERT
156,000
Hurler-Scheie (MPS-I)
ERT
340,000
Maroteaux-Lamy (MPS-VI)
ERT
377,000
Pharmacist’s Role
• Varied
• Patient & family needs may be
significant
• Information resource
what about . . .?
• Support
life-long, progressive condition
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Pharmacist’s Role
(2)
• Enzyme Replacement Therapy
• Product
• Supplies
• Home IV infusion support
vs. Home Care
vs. Private infusion providers
vs. hospital-based clinics
• Prophylactic agents
•
antihistamines
Elastomeric “Pump”
http://www.baxter.de/images/contentbilder
/aktuelle_themen_24072012_infusor.jpg
http://www.pppmag.com/documents/V7N5/infusion2.jpg
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Elastomeric “Pump”
http://www.baxter.cz/images/pro_odborniky_ve_zdravotnictvi/infuzory_1.jpg
Pharmacist’s Role
(3)
• Enzyme Replacement Therapy
• Monitoring Therapy
• Compliance
• Outcomes
•
•
Response to therapy
Progression (or regression)
of signs & symptoms
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https://igm.jhmi.edu/sites/default/files/lsd-program/Fig2_JohnsHopkinsLSDprogram.jpg
https://igm.jhmi.edu/content/johns-hopkins-lysosomal-storage-disease-program
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Pharmacist’s Role
(4)
• Other Medications for Symptom
or Supportive Care
•
•
•
•
•
Analgesics
Anti-inflammatory
Ophthalmic drops
Calcium & Vitamin D
Medical aids – canes, walkers
The Future is
Now?
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Alternative Therapies
• New therapies in the pipeline
• Oral alternatives
• Target alternative pathways and
enzyme enhancement
https://igm.jhmi.edu/sites/default/files/lsd-program/Fig2_JohnsHopkinsLSDprogram.jpg
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Pharmacist’s Role
(5)
• EARLY DETECTION
• Medication Assessments:
multiple medications for [seemingly]
unrelated conditions
• muscle, bone & mobility issues in early
adulthood
• Arthritis and digit contractions in
children
Early Detection
http://healthveda.com/wp-content/uploads/2011/02/Mucopolysaccharidoses.jpeg
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Early Detection
https://classconnection.s3.amazonaws.com/942/flashcards/652942/jpg/hunter's_syndrome1328275273629.jpg
Early Detection
http://www.paidiatros.gr/72-1/page2.6.jpg
http://www.google.ca/imgres?imgurl=http://www.orthospine.ru/getfile.aspx%253Fid%253D473%2526DBCode%253DUploadedFile&imgrefurl=http://www.orthospine.ru/default.aspx?did%3D289%26sid%3D148&h=23
5&w=352&tbnid=eMwqz2ilvT-GmM:&zoom=1&docid=TLbi3dXXNB9OoM&hl=en&ei=S59gVaCAKITYoASfooLACQ&tbm=isch&ved=0CC0QMygSMBI
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Early Detection
http://www.health-pictures.com/images2/gaucher's%20Disease.jpg
Early Detection
Hepato-splenomegaly
http://medicalency.com/gaucher_disease.jpg
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Newborn Screening
• A series of tests developed in 1961 by Dr.
Robert Guthrie to evaluate infants for
certain genetic anomalies, inborn errors
of metabolism, and other disorders.
https://sfari.org/images/in-brief/MetabolicScreeningArticle2.jpg/image_medium
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Newborn Screening
Congenital hypothyroidism
Phenylketonuria (PKU)
Galactosemia
Galactokinase deficiency
Maple Syrup Urine Disease
Homocystinuria
Biotinidase deficiency
Expanded Newborn Screening
• tandem mass spectrometry
http://www.sbu.edu/images/default-source/school-of-arts-and-sciences-chemistry/lc-ms-2_cropped.jpg?sfvrsn=2
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Expanded Newborn Screening
• tandem mass spectrometry
http://upload.wikimedia.org/wikipedia/commons/e/eb/MS_MS.png
Dried Blood Spot Testing
• Builds on the neonatal metabolic screen
(“Guthrie card”) method
drops of blood on filter paper
• Limited by small volume of blood on sample
• Monoclonal antibodies & polymerase chain
reaction (PCR) – improved sensitivity and specificity
http://www.perkinelmer.com/CMSResources/Images/44-130951bloodspot.jpg
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Dried Blood Spot Testing
(2)
• Available for expanded number of disorders
• Infectious diseases (HIV, hepatitis A & B)
• Lysosomal storage disorders
• Fabry (male)
• Gaucher
• Pompe
• Mucopolysaccharidosis Type I (MPS I)
Early Treatment
• Current treatment guidelines rely on
detection of symptoms and significant
disease
• cost of therapies
• Lack of LARGE controlled clinical trial
(CADTH response)
• Studies needed on benefits of early
intervention
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SUMMARY
• Our biochemical factory
• Lysosome as Human
Garburator (or recycler)
• LSD
• Pharmacist’s role
• The future is now!
Awareness
Suspect
Test
Refer
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Questions?
http://www.nature.com/nature/journal/v510/n7503/fig_tab/nature134
76_F3.html
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http://media.tumblr.com/72cd6684ad16987d118d3fd86fbdb73a/tu
mblr_inline_mpoiljzWSR1qz4rgp.jpg
http://usmle-review.org/lysosomal-storage.gif
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http://www.nature.com/nrneurol/journal/v9/n10/images/nrneurol.201
3.163-f1.jpg
http://www.nature.com/nature/journal/v510/n7503/images/nature13476-f2.jpg
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