3/29/2002

Nutritional Strategy

Protein break-down

Metabolic Regulators

Protein synthesis

Energy and amino acids

3/29/2002

CH2-CH2-C-O- Ca+

CH3

OHH3C

O

2

HMB- (����-hydroxy ����-methyl butyrate)

����

3/29/2002

HMB:

Theory: Cholesterol synthesis may limit cell growth/repair at certain times

HMB β-hydroxy-β-methylbutyrate

Leucine KIC CO2

Cholesterol

HMG-CoA

Cell membrane

3/29/2002

Human Studies w/ HMB

Adjunct for muscle building (Comparisons)SafetyCombinationsOther effects

3/29/2002

HMB and Resistance training

00.050.1

0.150.2

0.250.3

0.350.4

Net g

ain

lean

(%/w

k)

Nissen et al. 1996

Nissen et al. 1996

Panton 2000

Panton et al. 2000

Kreider et al. 1999

Jowko et al. 2001

Gallagher et al 2000

Slater et al. 2001

Vukovich et al 2001

3/29/2002

No adverse changes *Less negative moodEmotional

No adverse changesBlood hematology

No adverse changes*Lower cholesterol

Blood chemistry

No Adverse effects *Decreased BP Physical

Safety: 3-12 weeks

3/29/2002

Meta-Analysis:

Body composition Minimum 3-weeksMinimum trained 2x per weekPlacebo controlledStatistical information for ESProtein-(placebo issues)

3/29/2002

Meta-analysis: 250+ included

274Protein

242DHEA

323Androstenedione

3312Chromium

359HMB

3715Creatine

Quality score

Qualified studies

3/29/2002

Lean Tissue Gain

0

0.1

0.2

0.3

0.4

0.5

0.6

% g

ain

per

wee

k

CreatineHMB Chromium

Androstene...

DHEA Protein

Placebo Treatment*** ***

3/29/2002

Meta-Analysis

-0.10

0.00

0.10

0.20

0.30

Effe

ct S

ize

CreatineHMB

Chromium

Androstenedione

DHEAProtein

0.00

0.05

0.10

0.15

0.20

0.25

Effe

ct S

ize Lean Tissue

Gain

Strength Gain

Significant Effect size

3/29/2002

HMB and Creatine

+++Fat loss(weight training)

++-(risk of muscle

damage)

++(protect muscle)

Runner benefit

+-++++ (BP and cholesterol

lowered)

Health benefits

+++++++Lean gain (weight training)

CreatineHMB

3/29/2002

Minimizing Muscle damage

0

50

100

150

200

250

CPK

cha

nge

(%)

Pre Post Day 1 Day 2 Day 3 Day 4

Placebo

HMB

CPK after a 10K race

3/29/2002

Muscle stress results in tears in cell membrane

Muscle CPK leaks into the blood

CPK is 30-80% lowerLess muscle breakdown� Lower 3-

methylhistidine� Lower proteases

Less soreness

HMB effects on Damage

3/29/2002

Other observations

Less Protein turnover (muscle)Young and old: Men and womenEffect proportional to intensityImmune function improved

3/29/2002

Non exercising

Sedentary young people� HMB: No demonstrable effect� Creatine: No demonstrable effect

Wasting?

3/29/2002

WastingWastingNormalNormalProtein break-down

Protein synthesisProtein

synthesis

Protein break-down

Mechanism of wasting

3/29/2002

Age-related muscle mass

Age

Mus

cle

mas

s

100% of max

80% of max

70% of max

25 y 50 y

75 y<70%: Zone where Risk of Death is high

3/29/2002

Disease-related wasting

Most AIDS patients wasteNearly all stage 2-4 lung, pancreas, colon and upper GI cancers >10% muscle loss=risk

Question: Can targeted nutrition reverse wasting?

3/29/2002

Targeted Nutritional Strategy

Protein break-down

Slow

HMB

Protein synthesis

Enhance

Glutamine

Arginine

3/29/2002

Elderly protocol

Age ~78 yearsTwo replicate experimentsMostly women12 week studyEndpoints: lean tissue/mobilityAssisted living 2 g HMB/5 g Arg/ 1.5 g LysineOnce per day

3/29/2002

Body Composition changes

Body lean: +1 kg

-1.5-1

-0.50

0.51

1.52

2.53

% C

hang

e ov

er 1

2 w

ks

Iowa TN

Lean change

3/29/2002

Function(Get-Up & Go)

4 6 8 10 12

Get-Up & Go time (sec)

***+12 wks

Start

Start

+12 wks

PlaceboPlacebo

HMB/ HMB/ Arg /LysArg /Lys

3/29/2002

AIDS/Cancer Protocols

AIDS� Lost >5% BW� 36 subjects/8 wks

Cancer� Lost 10% BW� 40 subjects/8+wks

Mixture� 3 g HMB� 15 g Arginine� 15 g Glutamine

3/29/2002

AIDS/Cancer comparison

-0.7-1.1

2.5

1.4

-2.5

-1.5

-0.5

0.5

1.5

2.5

3.5Le

an g

ain

or lo

ss (

Kg)

AIDSsubjects

Cancer subjects

**

**

Placebo

HMB/Arg/Gln

3/29/2002

HMB + amino acid

Targeted nutritional strategy validVery slight wasting can be reversedVery sever wasting can be reversedMulti-center studies underway

3/29/2002

Muscle-Immune connection

-3

-2

-1

0

1

2

3

Placebo

HMB/Arg/Gln

Placebo vs HMB/Arg/Gln significantly different p<.01

Log changein viral titer

Viral titers in AIDS subjects treated for wasting

3/29/2002

Summary

250+ nutrition supplements marketed: � Only creatine and HMB meet scientific

threshold for resistance exercise~Double effectShort-term safetyNew applications: � Rational Combinations� Targeted