William E.

Code, MD, FRCPC

Denise Code, MSc, RD
Patricia A .L. Kongshavn, Ph.D

present

Resolving Pressure Ulcers

with a Bioactive Cystine-Rich and
Cost-Effective Protein Supplement

Continuing Medical Education Seminar

Sponsored by
NuMedTec
Toll free 877.687.2277
Resolution of Pressure Ulcers
For healing to occur, there are five major related
steps, each dependent on the prior step. All steps
require energy, protein and an anabolic stimulus.

1. Inflammation (white blood cells, soluble

factors – antibodies, ‘growth factors’)
2. Cellular Proliferation (angiogenesis,
fibroblast proliferation, epithelialization)
3. Connective Tissue Formation (collagen
production, interstitial matrix synthesis)
4. Wound Contraction (fibroblasts)
5. Wound Remodeling (increased collagen
cross-linking, etc.)
 Requirements for Successful
Resolution of Pressure Ulcers

Provide high quality protein for

rebuilding cells and tissues
Prevent or correct protein energy
malnutrition (PEM)
Maintain antioxidant defenses (raise
intracellular GSH*)
Strengthen the immune system to
fight against infection

*Glutathione is a tripeptide: glycine, glutamate and cysteine.

 Cystine & Glutathione
• Cystine (2 molecules of cysteine joined by a
disulfide bond –”bioactive cysteine”) is the
optimal form of the amino acid cysteine.
• Bioactive cysteine is needed to make
intracellular glutathione.
• Glutathione enhances the functioning of the
immune system and is a major antioxidant
and detoxifying agent.

SEE THE SLIDE: CYSTINE OR CYSTEINE

 Importance of Preserving the
Disulfide Bond in Cystine
Disulfide Bond
IN E
YS T
C
CYSTEINE CYSTEINE

„ Pasteurization/heat and instantization/stress break the

disulfide bond and destroy cysteine’s bioavailability,
causing cysteine to be oxidized in the gut during digestion
„ Once oxidized, cysteine becomes metabolized and loses
its bioavailability
Cystine or Cysteine
the Crucial Bioactive Difference Cysteine (CYS)
O O H
Cystine C
H
O O H N C H
C H
H H C H
N C H
H S H
H C H +
+ 2H
S

S S H

H C H H C H
H H
N C H N C H
H H
C C
O O H O O H

C6H12N2O4S2 C3H7NO2S

• Relatively rare in proteins

• Found in many proteins
• Useful to make glutathione, i.e. “bio-active”
• Useful source of energy
• Maintains positive N balance
Most Cysteine is Catabolized
during Digestion
„ Cysteine – minus disulfide bond is
catabolized during the digestive process
and not available for synthesis of
intracellular glutathione

„ Cystine – (bioavailable cysteine) disulfide

bond remains intact through digestion and
cystine preserved for intracellular
glutathione synthesis (i.e. “bioavailable”)
 Cystine Controls
Nitrogen Balance and LBM

• If cystine is available, conditions favor

retention of nitrogen and an increase in lean
body mass.
• If cystine is depleted, conditions favor loss of
nitrogen and a decrease in lean body mass.1

1DrogeW, Holm E. Role of cysteine and glutathione in HIV infection and other
diseases associated with muscle wasting and immunological dysfunction.
FASEB J. 1997 Nov;11(13) 1077-89.
 Cystine controls nitrogen balance.
Adapted from Droge W and Holm E. FASEB J 11:1077-89, 1997

amino acid pool

cyst(e)ine
α-ketoglutarate glutamate

H2O CO2
NH4+ glutamine
SO42/H+ HCO3
-
citrulline

carbamoylphosphate ornithine arginine

UREA

This diagram demonstrates the relationship between cystine and nitrogen balance to be as follows:
1. ↑ cystine, 2. ↑ protons (H+), 3. ↓ bicarbonate, 4. ↓ carbamoylphosphate, 5. ammonium ion
(NH4+) is saved; this results in positive nitrogen balance with maintenance or increase in weight.
1. ↓ cystine, 2. ↓ protons (H+), 3. ↑ bicarbonate (HCO3-), 4. ↑ carbamoylphosphate, 5.
ammonium ion (NH4+) enters into the urea cycle and is lost from the body; this results in negative
nitrogen balance with decrease in weight and possible cachexia.
The Cell
and Oxidative Stress

DNA

Mitochondria
Free radicals are
bi-products of
cellular metabolism
FUNCTIONS OF GLUTATHIONE

Oxidation
¾ The major antioxidant used by the cell to
neutralize and destroy damaging oxygen radicals
that are continually being generated by the
mitochondria during normal metabolic processes

¾ Also keeps vitamins C and E in their active state

¾ Plays a crucial role in maintaining an optimal pro-

oxidant/anti-oxidant balance within the cell
FUNCTIONS OF GLUTATHIONE

Detoxification
¾ A very important detoxifying agent , responsible
for ridding the body of many xenobiotics, toxins,
both exogenous and endogenous
FUNCTIONS OF GLUTATHIONE

Immune System Modulation

¾ Enhances the function of the immune system

¾ Glutathione is required in many of the intricate

steps of an immune response such as
multiplication of lymphocytes

¾ 50% of glutathione in lymphocytes is replaced

every 5-1/2 hours!
FUNCTIONS OF GLUTATHIONE

Cell Regulation
¾ Regulates many of the cell’s vital
functions such as:

- DNA synthesis and repair

- protein synthesis
- enzyme activation and regulation
 CLINICAL CONDITIONS
ASSOCIATED WITH LOW GLUTATHIONE VALUES

• Pressure Ulcers • Autism

• PEM • Hepatitis
• HIV with wasting • Ulcerative Colitis
• Diabetes • Crohn’s Disease
• Burns and Sepsis • COPD
• Cystic Fibrosis • Idiopathic Pulmonary Fibrosis
• Cancer • Adult Respiratory Distress Syndrome
• Chronic Fatigue Syndrome • Myocardial Ischemia

Low glutathione is also associated with pathogenesis of other degenerative diseases

including MS, Parkinson’s, Alzheimer’s, arteriosclerosis, cataracts and aging.
 Summary:
Benefits of a Bioactive Cystine Protein Supplement
for Resolution of Pressure Ulcers

1. High quality source of amino acids for synthesis of proteins

(growth factors, enzymes, structural proteins, collagen, and
many other proteins)
2. Rich source of cystine →GSH (counteracts oxidative stress,
regulates pro-oxidant/antioxidant balance in cells, etc.)
3. Rich source of cystine and other amino acids →maintain
LBM and counteract PEM
4. Strengthens the immune system (inflammation, infection)
 Case Studies

Resolution of Multiple Chronic Pressure Ulcers,

Improvement in Cognitive Function, and Reversal of Weight Loss
with a Bioactive Cystine-Rich Protein Supplement

Patricia Kongshavn, Ph.D.

Karen Wilkie, M.S.
 Time Course for Resolution of
Chronic Pressure Ulcer
Resolution of Chronic Pressure Ulcer
3
Patient: JL r Started Supplement

Medical History 2.5

A 91-year-old female patient with
dementia, osteoarthritis, peptic ulcer and 2
anxiety, had a stage III pressure ulcer on

Area (cm2)
the right buttock, measuring 3.4 x 3.2 cm
1.5
on admission to LTC. Approximately 8
months later the pressure ulcer had not
1
resolved. The patient was then given a
specific WPI supplement rich in bioactive
0.5
cystine, 37g BID. This supplement was
used until the ulcer was healed about
one month later. 0
-5 -4 -3 -2 -1 0 1 2 3 4 5

Weeks
Resolution of Multiple Chronic Pressure Ulcers and Improvement in Cognitive Function
Patient: DO
Medical History
A 64-year-old African male was transferred to LTC with dehydration, hyponatremia, urinary tract infection,
diabetes mellitus, history of multiple cerebral vascular accidents, severe contractures, multiple decubitus
ulcers, history of MRSA (methicillin-resistant Streptococcus aureus), aphasia, vascular dementia,
azotemia and possible sepsis. The patient was PEG tube fed.
The Medical Director reported that the patient had been transferred multiple times between the hospital
and the LTC facility and that multiple pressure ulcers had been present for over a year. He also reported
that the patient was not communicative in any manner, over this period.
The patient was placed on a specific WPI supplement rich in bioactive cystine, 37g BID until he was
transferred out of the LTC facility 35 days later.
Wound healing was monitored at weekly intervals. Owing to the large number of pressure ulcers being
observed, the wound sizes are shown only at a time shortly before starting the supplement and at the end
of the observation period. Some of the pressure ulcers healed and others improved greatly over the time
he received the supplement. (see table next slide)
Cognitive Observations
The patient was also observed to show surprisingly improved cognitive skills. Initially he was unable to
indicate his needs to the staff but, eight days after starting the supplement, he began to communicate with
facial expressions. At 14 days he was able to make eye contact. At 21 days he was alert, able to focus
on movements, and responded ‘yes’ and ‘no’ to statements by nodding and shaking his head. At 23 days
he also then responded to staff by raising his eyebrows and shrugging his shoulders.
 Time Course for Resolution of Time Course for Resolution of
Multiple Chronic Pressure Ulcers Multiple Chronic Pressure Ulcers
14 30

12
25

10 Lt Hip
Lt Buttock Site A 20
Area (cm2)

Lt Inner Buttock

Area (cm2)
8 Lt Buttock Site B
Rt Heel
15
6 Rt Buttock Site 1

10
4

2 5

0 0
-2 35 Days -8 35 Days

Time Course for Resolution of Time Course for Resolution of

Multiple Chronic Pressure Ulcer Multiple Chronic Pressure Ulcer

5 0.15

4
Rt Outer Ankle
Area (cm2)

Area (cm2)
Rt Buttock
0.1
Sit 2
3

2
0.05

0 0
-5 9 Days -8 30 Days
Resolution of Chronic Pressure Ulcer
Patient: GS Time Course for Resolution of
Medical History Chronic Pressure Ulcer

A 67-year-old male patient had a history of 6

insulin-dependent diabetes, coronary heart
disease, hypertension, chronic anemia, and
5
carcinoma of the prostate and bladder with r Started Supplement
r UTI
repeated urinary tract infections. In July
2003 both legs were amputated owing to 4

Area (cm2) .
progressive necrotizing soft tissue infections
of both lower legs, the right leg below the 3
knee and the left leg above the knee. A
decubitus ulcer on the coccyx was identified 2
and surgically debrided in July 2003 at
which time it measured 10 x 15 x 6 cm. This
1
wound failed to heal and 11 months later the
patient was started on a specific WPI
0
supplement rich in bioactive cystine, 37g
-5 0 5 10
BID until healing was complete. Weeks
Resolution of Non-Healing Wound
Patient: JS
Medical History
A 64-year old female patient had history of peripheral vascular disease, post-operative anemia,
coronary artery disease and hypertension, congestive heart failure, depression and anxiety,
hypercholesteremia, insomnia, tobacco use and failure to thrive. She was admitted with a chronic
non-healing wound with a history of MRSA
(methicillin-resistant Staphylococcus aureus),
resultant from a saphenous vein harvest graft Time Course for Resolution of
Non-Healing Wound
taken 6 months previously. The wound area
was large, necrotic/black in appearance, 70 s Started Supplement
suggesting some infection. It was debrided 60

twice, 3 days apart, and then an axillofemoral-

Area in sq inches
50
femoral-femoral bypass was performed with
40
bilateral profundoplasties, in order to restore
30
blood supply to the area. The wound measured
18 x 4 x 0.4 inches. The patient was 20

transferred from hospital to LTC ten days later. 10

After two days in LTC the patient was given one 0

0 5 10 15
serving of a specific WPI supplement rich in Weeks
bioactive cystine, 37g BID until the wound had
resolved. Throughout the healing process,
there were no signs of infection and the edema
was only moderate.
Resolution of Chronic Pressure Ulcer
Patient: LF
Medical History
A 76-year-old female patient with a history of Guillain-Barre syndrome, diabetes, chronic obstructive
pulmonary disease, depression, osteoarthritis, neuropathy, SIADH and anemia, was observed to have a
stage III pressure ulcer on the coccyx which failed to heal for 7 months. She was kept on an Alamo bed
during this period. She was placed on a specific WPI supplement rich in bioactive cystine, 37g BID until
healing was. Two weeks after starting the supplement she had improved sufficiently to be removed from
the Alamo bed. She continued to heal and the time course for complete healing is shown below.

Time Course for Resolution of

Chronic Pressure Ulcer
4.5

4
s Started Supplement
3.5

3
Week Comments
-3 5 sites of tunneling
Area (cm2)

2.5 -2 4 sites of tunneling

2 -1 3 sites of tunneling
0 3 sites of tunneling
1.5
1 No sites of tunneling
1 2 Granulating well
0.5

0
-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10

Weeks
Resolution of Multiple Pressure Ulcers
Time Course for Resolution of
Patient: VP
Chronic Pressure Ulcers
Medical History
25
s Started Supplement
A 79-year old female patient had a history
of coronary heart disease, essential
20
hypertension, chronic obstructive A
pulmonary disease, arthritis, chronic hip

Area (cm 2)
pain, mouth pain, depressive disorder and 15

dementia. She was admitted with a

fracture of the right femur at the distal end 10
of a previous total hip replacement and
was operated on to repair the femur. Ten
5 B
days later the surgical wound was healed
and the patient was transferred to LTC. At C
this time she was observed to have a 0
coccyxeal stage III pressure ulcer -5 0 5 10 15 20
Weeks
measuring 4 x 4 cm, and two smaller stage
III ulcers on the left buttock. She was A - coccyxeal stage III
started on a specific WPI supplement rich B - left buttock stage II
C - left buttock stage II
in bioactive cystine, 37g BID. She
developed two additional small ulcers on the left buttock on week four, both of which healed one week later.
After 5 weeks the left buttock ulcers were healed and she was switched to Ensure because the Director of
Nursing felt that she would finish healing without continuing the supplement. This did not happen, so at 13
weeks she was re-started on the supplement, 37g BID until the coccyxeal ulcer was healed.
Resolution of Coccyx Split Wound
Patient: FF
Medical History
An 85-year-old female patient with a history of Parkinson’s disease, dementia, hypothyroidism, urinary
tract infections and chronic renal failure, developed a pressure ulcer stage I (0.3 x 0.2 cm) which was
observed to have progressed to a coccyx split. Two months later she was placed on a specific WPI
supplement rich in bioactive cystine, 37g QD. The wound healed in 26 days.
Reversal of Weight Loss
Patient: AM
Medical history
A 91-year-old female had a medical history of chronic obstructive pulmonary disease, chronic hip
pain, congestive heart failure, depression, senile dementia, anemia, hypercholesterolemia and
hemiarthroplasty (right) hip.
The patient was only on ‘comfort care’.
She was placed on a specific WPI Time Course for Weight Gain
supplement rich in bioactive cystine, 37g 90
BID in order to counteract serious weight
loss and weighed at weekly intervals.
85
At a Care Conference approximately 3

Body Weight (lbs) -

weeks after starting the supplement, it 80
was stated that the patient had multiple
episodes of refusing meals. At that
75
same time the caregiver reported that
the patient had gained 9 lbs with the new
supplement, even though she only ate 70
u Started Supplement
23% of her meals. Moreover, despite
the fact that she was overcoming a bout 65
of pneumonia she still gained weight. -15 (5) 0 5 11
Weeks
 Improved Outcome for Healing of Pressure Ulcers
in Patients Fed a Cystine-Rich Protein Supplement

Before
Background
• Female, 92
• COPD, TIA, cerebrovascular accident, anxiety, aortic
stenosis, depression
• 2 Stage II pressure ulcers
• Treatment: 20g BID of a specific WPI supplement
rich in bioactive cystine
• Rate of Healing: coccyx 0.4 sq cm/mo, and left
buttock 10.7 sq cm/mo
39 Days Later
Days Days

0 (1 x 0.5) 0 (3 x 2.5)

42 Healed 21 Healed

Stage II, Coccyx Stage II, Left Buttock

0 0.25 0.5 0 4 8
Wound Area (cm sq) Wound Area (cm sq)
Complete Balanced Protein of Highest BV
Nutritional Information
Amino Acid Profile in grams
per 37g Serving of ProNutra® / 100 gm / 37 gm
Calories 368 136
Amino Amino Calories from fat 134 50
Quantity Quantity Total fat 15.00 g 5.55 g
Acid Acid Saturated fat 3.60 g 1.33 g
Polyunsaturated fat 0.62 g 0.23 g
ASP 2.286 TYR .558 Monounsaturated fat 5.16 g 1.91 g
Trans fatty acids 4.89 g 1.81 g
Cholesterol 1.60 mg 0.6 mg
THR 1.494 PHE .558 Total carbohydrate 30.00 g 11.10
Dietary fiber - -
SER .954 HIS .324 Sugars 3.37 g 1.24 g
Protein 49.00 g 18.13 g
GLU 3.546 LYS 1.710 Vitamin A 2780 IU 1000 IU
Vitamin C 695 mg 250 mg
Vitamin E 69 IU 25 IU
GLY .360 ARG .306 Thiamin ND ND
Niacin ND ND
ALA 1.008 PRO 1.134 Riboflavin ND ND
Calcium 280.0 mg 103.6 mg
Sodium 155.0 mg 57.4 mg
VAL 1.134 CYS .450 Potassium 498.0 mg 184.3 mg
Magnesium 96.0 mg 35.5 mg
ILE 1.224 MET .450 Phosphorus 340.0 mg 125.8 mg
Zinc 22.5 mg 8.3 mg
Iron 0.8 mg 0.3 mg
LEU 1.962 TRP .360
 ProNutra® (provides Bioactive Cystine) – Nutrition Facts
Serving Size 1 bottle 37g, Fruit Flavored

Nutritional Product
1 Bottle (37g) Nutrient RDI
Breakdown Level
Amount Per Serving Patented WPI 18g
Calories from Fat Vitamin A 5000 IU 1000 IU
Calories 140
50
Vitamin C 60mg 250mg
% Daily Value*
Vitamin E 30 IU 25 IU
Total Fat 6g 9%*
Calcium 1000mg 121mg
Saturated Fat 1.5g 7%*
Iron 18mg 2mg
Cholesterol 0mg 0%
Zinc 15mg 9mg
Sodium 55mg 2%
Omega 3 FA 11% of fat
Total Carbohydrate 10g 3%*
Omega 6 FA 22% of fat
Dietary Fiber 0g 0%
Ratio 6:3 2:1
Sugars 1g
< 65g (based on
Patented WPI 18g Total Fat 6g
2,000 calorie diet)
Vitamin A 20% ΠVitamin C 417% Calories 140
Calcium 12% ΠIron 11% INGREDIENTS: Patented WPI (Whey Protein Isolate), Shortening Powder (Partially
hydrogenated canola oil, lactose, sodium caseinate, dipotassium phosphate).
Vitamin E 84% ΠZinc 60% Erythritol (a sugar alcohol), Citric Acid, Natural & Artificial Flavors, Soy Lecithin,
Ascorbic Acid, Canola Oil, Alpha-Tocopheryl Acetate, Yellow Lake #6, Sucralose,
*Percent Daily Values are based on 2,000 calorie diet.
Your daily values may be higher or lower depending on your calorie needs:
Zinc Citrate, Vitamin A Palmitate.