Valproic acid for repurposing of familial adenomatous polyposis

1. Drug Information Center (DIC) Report on
Valporic acid repurposing for Familial
adenomatous polyposis
Presented by mesfin mamuye

2. • Introduction to Familial adenomatous
polyposis
• Introduction to Valproic acid
• Mechanism of action
• Black box warning
• summary
• Recommendation
• references

3.  also known as familial polyposis coli, is an
inherited disease characterized by the
appearance of numerous masses called
“polyps” throughout the large bowel.
 Other abnormalities involving other organs
such as the eyes, the bones or the skin can
also be present(© European Medicines Agency, 2013)

4. FAP affects males and females equally, and its
prevalence is reported to vary from 1 in 7,000
to 1 in 22,000 individuals. Individuals with FAP
account for less than 0.5 percent of all cases of
colorectal cancer.
The risk of developing the features associated
with the condition can be passed from
generation to generation in a family.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248206/

5.  Gardner syndrome-is characterized by the
presence of multiple gastrointestinal polyps.
 Turcot syndrome-associated with the
presence of gastrointestinal polyps and a
type of central nervous system (brain) tumor
known as medullo blastoma.
 Attenuated FAP -characterized by fewer
gastrointestinal polyps (average of about 30
polyps).
Bienz M. et al 2003 Mar 18;13(6):R215-6. Review.Citation on
PubMed

6.  abdominal pain,
 cramping, and
 vomiting (with blood in the vomit) or
bleeding with bowel movements
secondary to the presence of 100 or
more adenomatous polyps in the
small and/or large intestines.
https://www.mayoclinic.org/diseases-conditions/familial-
adenomatous-polyposis/symptoms

7.  Familial adenomatous polyposis is
caused by a defect in a gene that's
usually inherited from a parent.
 some people develop the abnormal
gene that causes the condition
 https://www.mayoclinic.org/diseases-conditions/familial-
adenomatous-polyposis/symptoms

8.  Your risk of familial adenomatous
polyposis is higher if you have a
parent,
 child,
 brother, or sister with the condition.
 https://www.mayoclinic.org/diseases-conditions/familial-
adenomatous-polyposis/symptoms

9.  Duodenal polyps. - grow in the upper part
of your small intestine and may become
cancerous.
 Peri ampullary polyps.- occur where the bile
and pancreas ducts enter the duodenum
(ampulla).
 Gastric fundic polyps. These polyps grow in
the lining of your stomach.
 Desmoids. These noncancerous masses can
arise anywhere in the body but often
develop in the stomach area
https://www.mayoclinic.org/diseases-conditions/familial-
adenomatous-polyposis/symptoms

10.  Screening;-
Sigmoidoscopy.sigmoid and rectum
Colonoscopy-to inspect the entire colon
Esophagogastroduodenoscopy (EGD) and
side-viewing duodenoscopy. to inspect
your esophagus, stomach and upper
part of the small intestine
CT or MRI-to evaluate desmoids tumors.
Genetic testing-You have family
members with FAP

11.  Surgery to remove polyps or
growths
 Chemotherapy
 Radiation
 Medications
 Investigational therapies
(https://www.chop.edu/conditions-
diseases/familial-adenomatous-polyposis)

12.  Valproic acid is a carboxylic acid
compound whose anticonvulsant activity
might be mediated by an inhibitory
neurotransmitter, GABA.
 Valproic acid might increase GABA levels
by inhibiting GABA metabolism or
enhancing postsynaptic GABA activity.
(https://www.drugbank.ca/drugs/DB00313)

13.  Absorption;. Rapid absorption from
gastrointestinal tract. Although the
rate of valproate ion absorption may
vary with the formulation
administered (liquid, solid, or
sprinkle)
 Protein binding-Concentration-
dependent, from 90% at 40 µg/mL to
81.5% at 130 µg/mL.

14.  Metabolism- is metabolized almost
entirely by the liver. In adult
patients on monotherapy, 30-50%
of an administered dose appears
in urine as a glucuronide
conjugate.
 Less than 3% of an administered dose
is excreted unchanged in urine.

15.  Half life-9-16 hours (following oral
administration of 250 mg to 1000 mg)
 Onset and Duration. Steady-state
serum levels are attained in 2–4 days.
 Bioaviability 90-100%
(https://www.drugbank.ca/drugs/DB00313)

16.  expected to stop (inhibit) the formation
of the new polyps and it might also
reduce the size of the existing polyps
 Act by induce acetylation of histones and
nonhistone proteins which are involved
in regulation of gene expression and in
various cellular pathways including cell
growth arrest, differentiation, DNA
damage and repair, redox signaling, and
apoptosis(Ju-Hee Lee2012)

17.  Valproic Acid may also work by
suppressing repetitive neuronal firing
through inhibition of voltage-sensitive
sodium channels. It is also a histone
deacetylase inhibitor.
 Valproic acid has also been shown to be
an inhibitor of an enzyme called histone
deacetylase 1 (HDAC1).
 HDAC1 is needed for HIV to remain in
infected cells. (Schwartz C. 2007
Mar;30(3):573-82. [PubMed:17273758] )

18.  For treatment and management of
seizure disorders, mania, and
prophylactic treatment of migraine
headache.
 In epileptics, valproic acid is used to
control absence seizures, tonic-clonic
seizures (grand mal), complex partial
seizures and FAP.

19.  Complex Partial Seizures;-IV (valproate
sodium): 10-15 mg/kg/day IV divided
q12hr infused over 1 hr;
maximum dose 60 mg/kg/day; do not
exceed 14 days (switch to PO as soon as
possible)
PO: 10-15 mg/kg/day PO initially;
increase by 5-10 mg/kg/day at weekly
intervals; may increase dose up to 60
mg/kg/day
https://reference.medscape.com/drug/valproic-acid-

20.  Simple & Complex Absence Seizures;-IV :
10-15 mg/kg/day IV divided q12hr
infused over 1 hr; maximum dose 60
mg/kg/day; do not exceed 14 days
(switch to PO as soon as possible)
PO : 15 mg/kg/day PO initially, divided
q6-12hr; increase by 5-10 mg/kg/day at
weekly intervals; may increase dose up to
60 mg/kg/day
https://reference.medscape.com/drug/valproic-acid-

21.  Migraine;-250 mg PO q12hr; adjust dose
based on clinical response, not to exceed
1000 mg/day
 Bipolar Mania;- 750 mg/day PO in divided
doses; adjust dose as rapidly as possible to
desired therapeutic effect; not to exceed 60
mg/kg/day
 FAP;-20-65mg/day
(Schwartz C. 2007 Mar;30(3):573-82. [PubMed:17273758] )

22. Most common:-Drowsiness,
Dizziness, Nausea,vomiting,
indigestion ,Diarrhea
Serious adverse effects include:
Bleeding, Low blood platelets
Encephalopathy, Suicidal behavior and
thoughts,Low body temperature
https://www.drugbank.ca/drugs/

23.  To date a total of 606 drugs are known to
interact with VPA, 12 major, 546 moderate,
and 48 minor interactions.Aspirin, caffeine,
and other salicylates can inhibit the clearance
of valproic acid and increasing its serum-free
concentration up to 4 times
 this may help to reduce the daily dose of VPA
but also increase its cytotoxicity when
administered with aspirin
(http://www.drugs.com/).

24.  hUMAN EXPOSURE STUDIES/ Valproic acid
(VPA) inhibits histone deacetylase and has
been reported to induce apoptosis in glioma.
/This study reports on/ 44 heavily pretreated
pediatric patients with high-grade glioma or
diffuse intrinsic pontine glioma who received
VPA as oral continues maintenance treatment
with individual dose adaptation.
https://toxnet.nlm.nih.gov/cgi-
bin/sis/search/a?dbs+hsdb:@term+@DOCNO+3582

25.  The tumor status when starting the drug was:
no measurable disease in 12, measurable but
stable disease in 12, and measurable
progressive disease in 22 patients. Average
trough blood levels of VPA were 99 mg/L.
The most frequent complaint was
somnolence (three patients), but no severe
toxicity was reported. [Wolff JE et al; J Neurooncol 90 (3):
309-14 (2008)] **PEER REVIEWED** PubMed Abstract

26.  One relapse patient responded, early
progression of disease was observed in three
frontline patients and in six relapsed patients.
Median overall survival duration for all
patients was 1.33 years, with large
differences between first-line (5-year overall
survival, 44%) and relapse therapy (5-year
overall survival, 14%). This shows that
valproate is safe in this patient population.
[Wolff JE et al; J Neurooncol 90 (3): 309-14 (2008)] **PEER
REVIEWED** PubMed Abstract

27.  Clinical Trial in Noncancerous Disorders
 Myeloid and Lymphoid Malignancies
 Solid Tumors
 Addiction
 Medullary thyroid cancer
 Muscle disorder
 http://clinicaltrials.gov

28.  Hepatotoxicity:-General Population: Hepatic
failure resulting in fatalities has occurred in
patients receiving valproate and its
derivatives. These incidents usually have
occurred during the first six months of
treatment. Serious or fatal hepatotoxicity may
be preceded by non-specific symptoms such
as malaise, weakness, lethargy, facial edema,
anorexia, and vomiting

29.  Birth Defects:-Birth defects have been found
in babies born to mothers who took valproate
while pregnant
 Pancreatitis:-Life threatening pancreatitis has
been reported in children and adults who
take valproate. Signs of pancreatitis include
severe abdominal pain, nausea, vomiting and
inability to keep food down. The College of Psychiatric
and Neurologic Pharmacists
 (January 2013)

30.  VPA is a molecule exhibiting a wide range of
effects upon various tissues, pathologies, and
patient profiles.
 This molecule is capable of altering the
expression of more than 20% of the
transcriptome in a tissue-dependent manner.
Therefore, it is currently very difficult to
anticipate all the effects that may occur
during treatments in mono- or polytherapies.
https://www.hindawi.com/journals/bmri/2010/479364/

31.  Use other drug such as sulindac ,celecoxib
because of valporic acid has serious side
effect other alternative drugs less ADR
 Balancing therapeutic potentialities with
serious side effects observed following use of
VPA to favor the advantageous effects will no
doubt prove to be a challenging and complex
issue for clinical management.
 https://www.hindawi.com/journals/bmri/2010/479364/

32.  Rosenberg G: The mechanisms of action of
valproate in neuropsychiatric disorders: can we
see the forest for the trees? Cell Mol Life Sci.
2017 Aug;64(16):2090-103. [PubMed:17514356]
 Schwartz C, Palissot V, Aouali N, Wack S, Brons
NH, Leners B, Bosseler M, Berchem G: Valproic
acid induces non-apoptotic cell death
mechanisms in multiple myeloma cell lines. Int J
Oncol. 2007 Mar;30(3):573-82.
[PubMed:17273758]
 (© European Medicines Agency, 2013)

33.  https://www.chop.edu/conditions-
diseases/familial-adenomatous-polyposis
 https://www.drugbank.ca/drugs/DB00313
 The College of Psychiatric and Neurologic
Pharmacists (January 2013)
 https://reference.medscape.com/drug/valpro
ic-acid-
 [Wolff JE et al; J Neurooncol 90 (3): 309-14 (2008)] **PEER
REVIEWED** PubMed Abstract

34.  Attard TM, Cuffari C, Tajouri T, Stoner JA, Eisenberg MT,
Yardley JH, Abraham SC, Perry D, Vanderhoof J, Lynch H.
Multicenter experience with upper gastrointestinal polyps
in pediatric patients with familial adenomatous polyposis.
Am J Gastroenterol. 2004 Apr;99(4):681-6.Citation on
PubMed
 Baglioni S, Genuardi M. Simple and complex genetics of
colorectal cancer susceptibility. Am J Med Genet C Semin
Med Genet. 2004 Aug 15;129C(1):35-43. Review.Citation
on PubMed
 Bienz M. APC. Curr Biol. 2003 Mar 18;13(6):R215-6.
Review.Citation on PubMed
 https://www.mayoclinic.org/diseases-conditions/familial-
adenomatous-polyposis/symptoms
 https://www.hindawi.com/journals/bmri/2010/479364/