OTC Flashcards
Medications to avoid in OTC
valproate, haldol, steroids
Amonnia levels in acute encephalopathy
> 200, often 500-1,000
What does OTC do in urea cycle
catalizes the reaction of carbamoyl phosphate and ornithine to form citruline in mitochondria
how is citruline involved in normal urea cycle
-converted to arginosuccinate, then arginine in hepatocyte cytoplasm
-eventually converted to urea and excreted
what does excess carbamoyl phosphate become when it is not converted by otc?
-orotic acid
Factors that can precipitate crisis
-infection
-high protein diet (atkins)
-prolonged physical activity
-post partum
-chemo
-starvation
-meds: depakote, haldol, steroids
-surgery
Supportive labs of OTC during crisis
-elevated ammonia (often 500-1000)
-elevated glutamine (>800)
-low citruline (single digits)
-high random urine orotic acid (>20)
-respiratory alkalosis
OTC gene therapy study name
Enhance
DTX301
Phase 3
Ages of enhance study
> 12 years old
Number of pts in enhance study
50
Follow up duration of pts in enhance
5 years of follow up
Primary endpoint of Enhance
to evaluate the efficacy of DTX301 on the improvement of otc function by improving ammonia levels
Secondary endpoints of enhance
-to evaluate the effect of DTX301 on 3 response categories
-to evaluate the effect of DTX301 on hyperammonemia indicator questionnaire
-to evaluate the effect of DTX301 on executive and verbal function
-to evaluate the effect of DTX301 on occurrence of HACs
-to evaluate the effect of DTX301 on plasma ammonia over time
-evaluate safety of DTX301
-evaluate for anti-otc antibodies
Enhance study design
-Cohort 1: gene therapy (n=25)
-Cohort 2: placebo (n=25)
-At week 64, groups switch treatments
-Long term follow up is at least 5 yrs, depending on which group pt was in
Enhance inclusion criteria
-male or female >12 yrs
-confirmed diagnosis of late onset OCT deficiency
-history of at least 1 episode of symptomatic elevated ammonia >100
-not actively hyperammonemia, not required acute treatment for an episode within last 4 weeks
-ammonia <200 at initial check
-plasma 24hr ammonia <4800 um/*h/L
-stable doses of nitrogen scavengers for at least 4 weeks
-stable protein restricted diet (daily protein intake does not vary >20% for at least 4 weeks)
-females must use contraception through wk 128
Enhance exclusion criteria
-ammonia >200
-liver disease (active hepatitis or severe cirrhosis)
-liver transplant
-active infection, HIV, chronic steroids
-AAV antibodies
-marked neuro deficit
-meds like depakote
-pregnant or breastfeeding
-current
How does sodium phenylbutyrate work
binds glutamine in mitochondria for excretion
How does sodium benzoate work
binds glycine in mitochondria for excretion
Which AAV is used in DTX301
AAV8
