Innovative Weight Loss

Executive Summary ........................ 2

The DHEA Dilemma ......................... 2

The Search for a Better DHEA:Dr. Henry Lardy ............................... 3

Pre-Clinical Development: Inductionof Thermogenic Enzymes ................ 4

Safety Studies:Pre-Clinical and Clinical ................... 5

Pharmacokinetics ........................... 5

How 7-Keto Works: The Storyof Thermogenic Enzymes ................ 6

Clinical Efficacy Studies .................. 8

Increased Metabolism .................... 10

Weight Loss Claims ....................... 10

Patented for Weight Loss .............. 10

DSHEA Notification ........................ 11

Manufacturing and Quality ............ 11

7-Keto - The Keystone ForToday’s Weight Loss Formulas ....... 11

References ................................... 12

The data presented in this book is provided forinformational purposes only. Although webelieve the data to be accurate, the readershould make their own determination aboutthe adequacy or accuracy of all supportinginformation. The information in this book is notintended to substitute for legal adviceregard ing hea l th cla ims under anyfedera l , state or local laws.

These statements have not been reviewed bythe Food and Drug Administration. This productis not intended to diagnose, treat, cure or pre-vent any disease.

7-Keto is a t rademark of Humanet icsCorporation.

w w w . h u m a n e t i c s c o r p . c o m

In today’s weight loss marketplace, both manufacturers and consumers

are looking for products that are safe as well as effective. 7-Keto™ has

filled this space by offering four key benefits:

• Excellent safety profile.

• Industry leading efficacy.

• Boosting metabolism without stimulants.

• World-class clinical trial pedigree.

7-Keto (a trade name for the compound 3-acetyl-7-oxo dehydroepi-

androsterone or 7-oxo DHEA) is a substance found naturally in the body

and its presence in human urine was documented in 1958. It is metabo-

lized from the hormone DHEA, and like DHEA, it is known to decline with

age. Supplementing with 7-Keto is simply putting back what time and

Mother Nature have taken away.

Humanetics Corporation, the developer of 7-Keto, has invested significant

time and money into a methodical research program that has spanned

over the past 16 years. Among other things, this research has included

rigorous toxicology, pharmacokinetic and human safety trials. These

studies strongly support that 7-Keto is non-toxic, cannot accumulate in

the body over time, does not affect any hormone levels and is free of any

serious side effects. Of even more importance, 7-Keto has been sold

commercially as a dietary supplement since 1998 and, in this time, has

not been linked to any serious adverse effects.

Being safe is of utmost importance; however, to market a compound

requires that it have a benefit to the consumer. A patent was issued in

1994 for the use of 7-Keto for effecting weight loss and preventing

weight gain. The patent is built upon the discovery that 7-Keto is a potent

activator of 3 important thermogenic enzymes. These enzymes are

known to play an important role in helping the body convert stored fat to

energy. The first of two randomized, double-blinded, placebo-controlled

(“RDBPC”) weight loss clinical trials was conducted in 1999. This study

indicated that 7-Keto increased weight loss over an eight week period by

a factor of three times versus placebo. A second trial was commissioned

in 2000 to confirm these results. The second trial, also RDBPC, confirmed

that weight loss over an eight week period could be increased by a fac-

tor of 3 times. Importantly, each of these studies confirmed that more

than 80% of the weight lost was fat. Each study controlled for diet, exer-

cise and diuresis effects and both have been published in international

peer reviewed journals.

Results of an additional human clinical study reveal that administration of

7-Keto to overweight adults in conjunction with a calorie restricted diet

will effectively reverse the decline in resting metabolic rate (RMR) nor-

mally associated with dieting. 7-Keto plus a restricted calorie diet

demonstrated an increase in RMR by 1.4% above baseline levels versus

a 3.9% decrease in RMR in the restricted calorie diet only group.

Therefore, the addition of a 7-Keto to a restricted calorie diet produced a

statistically significant 5.4% increase in daily RMR when compared to a

calorie-restricted diet only.

The documented science behind 7-Keto provides strong support that

it is safe and effective for helping consumers lose weight and maximize

results from diet and exercise. The purpose of this document is to pro-

vide you with a brief but thorough overview of this science. Read

on and find out why 7-Keto is becoming the ingredient of choice for major

nutraceutical marketing companies.

The DHEA DilemmaDHEA, also known as dehydroepiandrosterone, is synthesized in the adre-

nal cortex from cholesterol via pregnenolone by the action of an enzyme

called cytochrome P450. It is the most abundant adrenal steroid in

humans and is the precursor for many important steroid hormones, which

includes estrogen and testosterone. In contrast to cortisol and other adre-

nal steroids, DHEA levels decline with age. Levels of DHEA increase

through the second decade of life and then begin to decline to negligible

amounts at ages greater than 70 years. We experience a 40% reduction

in DHEA levels between ages 20 and 40. Since DHEA is the major andro-

gen precursor in humans, men have 30% higher DHEA levels than women

throughout their lives.

Executive Summary

3

Recognizing that the bioactivity of DHEA must rest with one or more of its many metabo-

lites, Dr. Henry Lardy led the search for more specific and active metabolites

of DHEA. Dr. Lardy is Vilas Professor Emeritus of the Institute for Enzyme Research at the

University of Wisconsin in Madison. Dr. Lardy is renowned for his research on DHEA deriv-

atives and has published over 400 studies in peer-reviewed scientific journals.

To search for possible metabolites of DHEA that might have greater biological activity,

greater specificity, and fewer propensities to form sex hormones, Dr. Lardy initiated a

program assaying the derivatives of DHEA. The activity of 150 of these metabolites was

monitored by measuring the induction of two thermogenic enzymes, mitochondrial glyc-

erol-3-phosphate dehydrogenase and cytosolic malic enzyme. The results of this land-

mark study were published in the journal Steroids in 1998 and revealed that many of

these steroids did not induce the activity of these thermogenic enzymes whereas the 7-

oxo DHEA (“7-Keto”) metabolite did. In fact, 7-oxo DHEA was 2.5 times more active than

DHEA at inducing the activity of these thermogenic enzymes. More importantly,

Dr. Lardy discovered that in contrast to DHEA, the 7-oxo DHEA metabolite was not con-

vertible to compounds with estrogenic or androgenic activity.

7-oxo DHEA is a naturally occurring DHEA metabolite in humans and was first discovered

in the urine of human volunteers in 1958 by Gallagher. In later work by Marenich, it was

discovered that the urinary excretion of 7-oxo DHEA declines with age in a similar man-

ner to its parent steroid DHEA.

Based on these discovered advantages, the 7-oxo DHEA metabolite was chosen for fur-

ther study as a weight loss ingredient.

The physiological significance of the variation in DHEA

levels with advancing age is interesting and many

researchers have noted some important correlations.

As DHEA levels decline with age:

• The incidence of obesity increases.

• Reproductive function decreases.

• Basal metabolic rate decreases.

• Immune function decreases.

• Age related skin changes increase.

To avoid many of these age-related maladies, many

have advocated supplementing the diet with DHEA

to maintain plasma levels at a more youthful level.

Since DHEA is a hormone precursor and not a “true”

hormone itself, the actions of DHEA must be attributed

to its many metabolites. It is for this very reason that

supplementation with DHEA is more difficult than

it may initially appear. For example, while supple-

menting with DHEA for a particular indication, an indi-

vidual may suffer side effects in another organ system

due to the accumulation of unwanted active hormone

metabolites, such as testosterone or estrogens.

The Search for a Better DHEA

4

In 1993, Bobyleva et al demonstrated in a rat model that 7-oxo DHEA

caused an increase in liver catalase activity, rate of mitochondrial sub-

strate oxidation and fatty acyl-CoA oxidase activity. Brand et al report-

ed in 1988 that the elevated thermogenesis associated with hyperthy-

roidism may result from an increase in proton conductance across the

mitochondrial membrane causing a lower membrane potential and

greater thermogenesis. In 1998, Lardy et al reported that 7-oxo DHEA

is a more active inducer of glycerol-3-phosphate dehydrogenase

(G3PD) and malic enzyme than its parent steroid DHEA.

Considering that 7-oxo DHEA and thyroid hormone activate similar

mitochondrial and cytosolic thermogenic enzymes, Bobyleva et al then

studied 7-oxo DHEA using a similar rat system model. Sprague-Dawley

rats which were treated with respiratory inhibitors (succinate and

G3PD) showed that when further treated with 7-oxo DHEA, they expe-

rienced a more rapid decline in membrane potential, indicating

enhanced thermogenesis. Realizing that the pharmacokinetic profile of

7-oxo DHEA is similar to that of thyroid hormone, these investigators

went on to test 7-oxo DHEA in both the euthyroid and hypothyroid rat.

7-oxo DHEA had no effect in the euthyroid rats but restored mitochon-

drial function in the hypothyroid rat. These investigators were not cer-

tain of the mechanism by which 7-oxo DHEA was able to exert these

effects, but since 7-oxo DHEA had no influence at all when added

directly to the test systems, they speculated that 7-oxo DHEA is con-

verted to a metabolite that is recognized by a member of the

steroid/thyroid hormone superfamily of receptors. Since it is known

that 7-oxo DHEA does convert to other in vivo metabolites, this concept

remains a viable explanation.

This extensive pre-clinical investigation demonstrated 7-oxo DHEA’s

ability to enhance thermogenic enzyme activity at multiple levels and

led to its further investigation as a weight loss ingredient in humans.

Pre-Clinical Development: Induction of ThermogenicEnzymes

The Science of

Supplements

5

Safety StudiesPrior to any commercial sale of 7-oxo DHEA, Humanetics Corporation

commissioned a series of thorough toxicology evaluations. These studies

were conducted using pharmaceutical industry protocols. They started

with basic pre-clinical toxicology studies and culminated in a Phase I

safety trial in humans. The majority of these studies have been published

in peer review journals. (See References)

The preclinical

program consist-

ed of four toxicol-

ogy evaluations,

the design and

results of which

can be seen in

the table. These

studies indicat-

ed that

7-Keto is not

toxic and does not a l ter any significant body organs or processes,

even at extremely large doses.

Confirmation of the lack of toxicity in our preclinical studies led to the

confidence to put 7-Keto into an escalating dose human safety trial. This

double-blind and placebo-controlled trial was conducted at the Chicago

Center for Clinical Research. The results were published in Clinical

Investigative Medicine 2000, and indicate that 7-Keto is safe for human

consumption at doses up to 200mg per day. The conclusion of the prin-

cipal investigator was as follows, “[7-Keto]…which is not converted to

estrogens and androgens, was found to be safe and well-tolerated…at

doses up to 200mg/d. [7-Keto] was found to lack any of the clinically sig-

nificant hormone elevating action that has been reported with DHEA sup-

plementation.”

Careful toxicology and safety studies are paramount to ensuring the basic

premise of safety for any ingested compound, which is especially true in

today’s market. However, most dietary supplements lack this level of

thorough study and many lack even basic toxicology research. As many

weight loss compounds come under scrutiny for safety, 7-Keto provides

peace of mind that it can be used safely.

PharmacokineticsA complete pharmacokinetic analysis of 7-oxo DHEA was performed as

part of the clinical safety study performed by Davidson. The analysis was

under the direction of Ronald Sawchuk, PhD of the University of

Minnesota-College of Pharmacy.

Similar to DHEA, 7-oxo DHEA is rapidly sulfated to 7-oxo DHEA-sulfate in

the body. An analytical method was developed for quantitation of

7-oxo DHEA-sulfate in human plasma. This was an HPLC method, which

utilized calibration curves for 7-oxo DHEA-sulfate in the range of

10 to 500 ng/ml.

Trough levels were measured after each escalating dose sequence;

0, 50, 100 and 200 mg per day. Trough plasma concentrations increased

proportionally to the daily dose. Mean trough levels (15.8ng/ml) after

1 week of dosing at 200 mg/day were similar to those determined after

4 weeks of dosing (16.3 ng/ml). This indicated that the ratio of the for-

mation rate of this metabolite to its elimination clearance is constant dur-

ing multiple dosing and does not accumulate.

After a twelve-hour washout period all twenty-two subjects were given a

single dose of 7-oxo DHEA at 100 mg and plasma levels were obtained

at 0.25, 0.50, 1.0, 2.0, 4.0, 6.0 and 12.0 hrs after the dose. The mean

plasma concentrations are depicted in the chart below and demonstrate

a peak plasma level of 158 ng/ml which occurred at 2.2 hours after the

dose. The average elimination half-life was determined to be 2.17 hours.

Based on this data, the dosing regime of twice a day was set and remains

the ideal dosing schedule centered around steady state blood levels.

Lastly, simulations of plasma concentrations of 7-oxo DHEA-3-sulfate

were performed to represent the regimens employed in the dose escala-

tion phase of the study. A one-compartment model was assumed with

first order absorption and no lag phase. The results of these simulations

using this pharmacokinetic model showed that there was good agree-

ment between the simulated and measured means of the trough plasma

levels and also the plasma concentrations of a single 100mg oral dose.

This pharmacokinetic analysis is very valuable because it describes

exactly how the body absorbs, metabolizes and excretes 7-oxo DHEA.

It reveals that 7-oxo DHEA is rapidly absorbed and converted to its sul-

fate derivative, it reaches peak plasma concentrations in 2.2 hours and

has a half-life of 2.17 hours. There is no accumulation with repeated dos-

ing and with twice daily dosing should reach a steady state plasma level

in 11 hours.

6

Escalating Dose

Oral Gavage in

Thermogenesis is a term which describes the creation of heat in mam-

mals. Heat is a form of energy produced when the food we eat is metab-

olized in the cells of our body. Chemical energy, in the form of adenosine

triphosphate (ATP) is also produced in this reaction and is the body’s bio-

logically useful energy. ATP is the “energy currency” of the cell and is

used to drive all energy requiring reactions including the synthesis of pro-

teins, carbohydrates and fats. It also causes muscles

to contract and nerves to conduct.

ATP, while a good energy packet, is not a good fuel storage molecule, as

it is used quickly after being formed. Better storage forms of energy are

glycogen and triglycerides. Glycogen is broken down to glucose and

triglycerides are broken down to fatty acids, both of which are readily uti-

lized for energy. Of importance, is that any food not utilized for energy is

subsequently stored for use later, and mostly as fat since it is the most

efficient energy storage form at 9 kcal/gm. The synthesis of triglycerides

requires glycerol (from carbohydrates), fatty acids and energy from ATP.

The production of energy from glucose and fatty acids occurs at the cel-

lular level with glycolysis (glucose metabolism) occurring in the cytosol of

the cell and fatty acid oxidation in the mitochondria of the cell. The mito-

chondria is often considered the “powerhouse” of the cell, and most cells

involved with fatty acid metabolism are in the liver. Acetyl CoA, an essen-

tial substrate for energy production, is an end product of both glycolysis

and fatty acid metabolism. The enzyme required for the oxidation of fatty

acids to acetyl CoA is fatty acyl CoA oxidase.

Acetyl CoA, as a substrate in the Krebs cycle, produces NADH, NADPH and

FADH2, which are reducing agents that supply hydrogen atoms or elec-

trons in chemical reactions and are used for ATP production in the mito-

chondria via a process called oxidative phosphorylation. The oxidation of

fatty acids also produces NADH and FADH2. Each molecule of NADH pro-

duces 3 ATP’s within the confines of the mitochondria. NADH is also pro-

duced in the cytosol (outside of the mitochondria) but needs to be trans-

ported into the mitochondria in order to be converted to energy. This

transport mechanism is called the “glycerol-3-phosphate shuttle” and

requires the enzyme glycerol-3-phosphate dehydrogenase to catalyze

the reaction. This “shuttle” requires energy and the end result is that

cytosolic NADH is only able to produce 2 ATP’s per mole and the rest of

the energy is released as heat. This is therefore a more “thermogenic”

utilization of NADH (the reaction produces less ATP and more heat, also

called “futile cycling”).

For the purpose of this discussion we will also include the reaction which

converts malic acid (a Krebs cycle intermediate) to pyruvate and NADPH.

This conversion occurs in the cytosol and requires an enzyme called

malic enzyme. This reaction is important since it not only produces

cytosolic NADPH but also produces heat.

Compounds with thermogenic activity are substances which foster the

production of heat relative to the production of ATP. Very often, these

compounds have the ability to enhance the activity of certain enzymes

which drive these thermogenic reactions. The quintessential thermogenic

compound is the thyroid hormone, thyroxin (T4). Thyroxin has the ability

to “uncouple” oxidative phosphorylation (less ATP production and more

heat production) by enhancing the activity of glycerol-3-phosphate dehy-

drogenase and malic enzyme.

Research by Lardy and others has shown that 7-oxo DHEA is able to

enhance the activity of three thermogenic enzymes: glycerol-3-phos-

phate dehydrogenase, malic enzyme and fatty acyl CoA oxidase.

Thermogenesis

How 7-Keto Works:Enhancing Thermogenesis

7

Glycerol-3-phosphate

dehydrogenase

The activation of glycerol-3-phosphate

dehydrogenase results in an up-regu-

lation of the glycerol-3-phosphate shut-

t le . Th is , in turn , favors the con-

vers ion o f cy toso l i c NADH to a

pathway of less ATP production and more

heat production.

Malic Enzyme

The activation of malic enzyme results in

the conversion of malic acid to pyruvate

and NADPH in the cytosol. This results in

an excess of NADPH in the cytosol, which

is subsequently transported into the mito-

chondria where it is converted to ATP and

heat. This is a thermogenic effect since

more heat is produced relative to ATP

production due to the cytosolic origin of

the reaction.

Fatty Acyl CoA Oxidase

Lastly, the activation of fatty acyl CoA oxi-

dase results in an enhancement of fatty

acid breakdown.This reaction results in

the production of acetyl CoA, NADH and

FADH2. This drives the cell to utilize fatty

acids for energy, which in turn promotes

the breakdown of triglycerides, the body’s

fat storage moiety. The acetyl CoA, NADH

and FADH2 produced in this reaction are

subsequently converted to ATP and heat,

and at a faster rate than normally expect-

ed. The end result is an increased pro-

duction of heat considering the inefficien-

cy of the reaction.

All three of these enzyme activations

drive energy producing substrates in a

direction of less efficient ATP production

relative to heat production. This is the

biological definition of thermogenesis.

In addition, they promote the utilization of

fat stores for energy and heat production.

Hence, 7-Keto’s ability to enhance

thermogenes is and th rough tha t

mechanism, accelerate the utilization

of fat stores for heat production.

8

Two independently conducted clinical trials support the effectiveness

of 7-Keto for weight loss. Both trials were double-blind and placebo-con-

trolled. Subjects were controlled for diet, exercise and body water, so

that the true weight loss effect of 7-Keto could be isolated. Both studies

showed a statistically and clinically significant reduction of weight

through the use of 7-Keto versus placebo. Both studies have been pub-

lished in peer-reviewed journals.

A Randomized, Double-Blind, Placebo-Controlled Study of 3-Acetyl-7-Oxo-

Dehydroepiandrosteronein Healthy Overweight Adults

Douglas S. Kalman, Carlon M. Colker, Melissa A. Swain,

Georgeann C. Torina, and Qiuhu Shi

Peak Wellness

The purpose of this study was to determine weight loss of 3-acetyl-7-oxo-dehydroepiandrosterone (7-oxo-DHEA) in healthy overweight adultscompared to placebo.

In this double-blind, placebo controlled protocol, 30 adults (28 womenand 2 men; mean age, 44.5 ± 11.5 years) with a mean body mass indexof 31.9 ± 6.2 kg/m_ were randomly divided into 2 groups of 15: Group1 received 7-oxo-DHEA 100 mg twice daily and Group 2 received place-bo for 8 weeks. All subjects participated in an exercise training program3 times per week. Exercise session consisted of 60 minutes of crosstraining (aerobic and anaerobic exercise) under the supervision of anexercise physiologist. In addition, each subject was instructed to followa diet of ~ 1800 kcal/d (20 kcal/[kg · d]) by a registered dietitian.Subjects received biweekly dietary counseling to encourage compliance.Study participants underwent serum multiple-assay chemistry testing,as well as body composition, blood pressure, and dietary analysis atbaseline, week 4 and week 8.

Of the 30 subjects who entered the study, 23 completed the 8-week pro-tocol. Seven subjects dropped out for personal reasons unrelated to thestudy. Group 1 lost a significant amount of body weight compared withGroup 2 (-2.88 kg vs – 0.97 kg; P = 0.01) over the 8 weeks. Group 1 alsoachieved a significant reduction in body fat compared with Group 2 (-1.8% vs –0.28%; P < 0.01). There were no significant changes in levelsof thyroid-stimulating hormone (TSH) or thyroxine (T4) in either group. Inaddition, no significant changes were observed in vital signs, bloodsugar, testosterone and estradiol levels, liver and renal function, or over-all caloric intake during the study. No subjective adverse effects werereported throughout the study.

The results of the study suggest that 7-oxo-DHEA combined with mod-erate exercise and a reduced-calorie diet significantly reducesbody weight and body fat compared with exercise and a reduced-caloriediet alone.

Clinical Efficacy Studies

9

LossWeight

The Effect of 7-Keto Naturalean™

on Weight Loss: A Randomized, DoubleBlind, Placebo Controlled Trial

John L. Zenk, MD, Tami R. Helmer, MD, Laurie J. Kassen, LD, RD,

and Michael A. Kuskowski, PhD

Minnesota Applied Research Center

A natural metabolite of dehydroepiandrosterone (DHEA), 3-acetyl-7-oxo-dehydroepiandrosterone (7-oxo DHEA), has been shown to be effective inenhancing weight loss when combined with a diet and exercise program.

This study assessed the effects of a formula containing 7-oxo DHEA,(200mg/day) on weight loss, body composition, and basal metabolic rate(BMR) in overweight patients following a weight-reduction diet and exer-cise regimen.

In this prospective, randomized, double-blind, placebo-controlled trial,healthy, overweight adults were given the formula containing 7-oxo DHEAor a placebo and followed a calorie restricted diet (105 kJ/kg) and anexercise program for 8 weeks. Body weight, body composition (by bio-electric impedance), and BMR (by indirect calorimetry) were measured atbaseline, week 4 and week 8. A thyroid panel was done at baseline andweek 8.

Of 35 healthy, overweight adults enrolled, 33 completed the study(12 men, 21 women; age, 40-69 years; body mass index [BMI],27.0-42.7 kg/m2). Patients taking 7-Keto Naturalean lost significantlymore weight after 8 weeks than those taking placebo (mean ± SD loss,2.15 ± 2.38 kg and 0.72 ± 2.12 kg, respectively) (P=0.038).The change in BMI in the 7-Keto Naturalean-treated group was signifi-cant compared with the change in the placebo group (mean ± SDdecrease, 0.71 ± 0.79 kg/m2 and 0.01 ± 1.05 kg/m2, respectively)(P=0.036). There were no other statistically significant differencesin any of the other measured variables. 7-Keto Naturalean was well tol-erated, and there were no significant adverse events.

This formula containing 7-oxo DHEA when combined with a reduced-calorie diet and an exercise program resulted in a significant weight losscompared with diet and exercise alone.

10

Increased MetabolismIn 2004, a clinical study involving 45 subjects was performed to evaluate

the effect of 7-oxo-DHEA on resting metabolic rate (RMR). The results

revealed that administration of 7-Keto to overweight adults in conjunc-

tion with a calorie restricted diet effectively reversed the decline in rest-

ing metabolic rate (RMR) normally associated with dieting. 7-Keto plus a

restricted calorie diet demonstrated an increase in RMR by 1.4% above

baseline levels versus a 3.9% decrease in RMR in the restricted calorie

diet only group. Therefore, the addition of 7-Keto to a restricted calorie

diet produced a statistically significant 5.4% increase in daily RMR when

compared to only a calorie restricted diet.

Most weight loss programs are designed to manipulate diet and appetite,

but there is a growing rationale to support efforts to increase energy

expenditure (RMR) as a tool to enhance the results of a weight loss pro-

gram. 7-Keto achieves this thermogenic effect by directly up-regulating

the activity of fat burning enzymes rather than through the use of stimu-

lants. Thus, with the addition of 7-Keto, dieters attempting any weight

loss program can enjoy more success, and more quickly achieve their

weight loss goals.

Weight Loss ClaimsMarketers of weight loss supplements are growing increasingly aware of

the need for well-substantiated claims. Marketing a product in the weight

loss category is a difficult proposition for today’s nutraceutical compa-

nies. In a cluttered market full of outrageous claims, 7-Keto provides a

clear set of weight loss claims that are well supported by competent

research:

• 3 Times more weight loss than diet and exercise alone

• Majority of weight loss is fat loss

• Promotes weight loss without the use of stimulants

• Awarded a U.S. patent for weight loss

• Gives you what the body naturally produces

• Clinically proven weight loss

• Safe, when used as directed

• Activates 3 thermogenic enzymes

• Natural “7-Keto” levels decline with age

• Increases metabolism by 5.4% without stimulants

Patented for Weight LossIn 1994 Humanetics Corporation received United States patent number

5,296,481 for the use of a select class of compounds for use in weight

loss. This class of compounds includes 7-Keto and many of its natural

metabolites and other derivatives. Since this time, Humanetics has filed

and received international patents which protect the use of 7-Keto for

weight loss in Canada, Europe, Japan and Australia.

Humanetics sells 7-Keto only to those companies that enter a license

agreement. This process is used to protect all marketers of 7-Keto prod-

ucts, insuring that no mis-branded, adulterated, or potentially unsafe

ingredients enter the market.

Metabolism

11

DSHEA NotificationPrior to marketing 7-Keto as a dietary supplement, it was submitted for

a review of safety to the Food and Drug Administration (FDA) in the form

of a New Dietary Ingredient (NDI) premarket notification. This document

can be viewed at the FDA website and it received no comments or con-

cerns from the FDA. Subsequent to this initial filing, another NDI premar-

ket notification has been filed specific to the use of 7-Keto for weight loss

in adults at the prescribed dosage. This notification received no com-

ments or concerns from the FDA.

Manufacturing & Quality7-Keto is manufactured using GMP guidelines to exacting specifications.

These specifications include a review of not only the purity and potency

of each lot manufactured, but also a thorough examination of all impuri-

ties. It has been proven in many infamous and unfortunate cases, that

lack of control in the manufacturing process leading to unknown impuri-

ties can have significant and serious adverse effects. Humanetics goes to

the added expense of a 100% test program prior to release of any lot.

This test program is conducted at an independent analytical laboratory

and certifies 14 different quality specifications.

7-Keto™-The KeystoneFor Today’s Weight LossFormulas.Many weight loss ingredients have come and gone over the past five

years. Most have faded in popularity due to many factors including lack

of results, enforcement actions by the Federal Trade Commission due to

lack of claims substantiation, and concerns over safety and liability.

7-Keto continues to grow as a top selling weight loss ingredient for

today’s nutraceutical manufacturers because it offers the published doc-

umentation necessary in the weight loss marketplace. In addition,

it can back up its claims for safe and effective weight loss, which is crit-

ical for longevity of any dietary ingredient.

the winning com-bination forweight loss

a balanced diet

regular exercise

and 7-Keto™

12

13 Copyright 2005 Humanetics Corporation

Pre-Clinical Studies

Bobyleva V, Bellei M, Kneer N, Lardy H. The Effects of the Ergosteroid 7-oxo-dehy-

droepiandrosterone on Mitochondrial Membrane Potential: Possible Relationship to

Thermogenesis. Arch Biochem Biophys 1997;341:122-128.

Miyamota H, Yeh S, Lardy H, Messing E, Chang C. Delta-5-Androstenediol is a

Natural Hormone With Androgenic Activity in Human Prostate Cancer Cells.

Proc Natl Acad Sci 1998;95:11083-11088.

Lardy H, Partridge B, Kneer N, Wei Y. Ergosteroids: Induction of Thermogenic

Enzymes in L i ve r o f Ra ts Trea ted w i th S te ro ids Der i ved f rom

Dehydroepiandrosterone. Proc Natl Acad Sci 1995;92:6617-6619.

Lardy H, Kneer N, Wei Y, Partridge B, Marwah P. Ergosteroids II: Biologically Active

Metabolites and Synthetic Derivatives of Dehydroepiandrosterone. Steroids

1998;63:158-165.

Reich IL, Lardy H, Wei Y, Marwah P, Kneer N, Powell DR, Reich HJ. Ergosteroids III:

S y n t h e s i s a n d B i o l o g i c a l A c t i v i t y o f S e c o - S t e r o i d s R e l a t e d t o

Dehydroepiandrosterone. Steroids 1998;63(10):542-553.

Marwah P, Marwah A, Kneer N, Lardy H. Ergosteroids IV: Synthesis and Biological

Activity of Steroid Glucuronosides, Ethers, and Alkylcarbonates. Steroids

2001;66(7):581-595.

Reich IL, Reich HJ, Kneer N, Lardy H. Ergosteroids V: Preparation and Biological

Activity of Various D-Ring Derivatives in the 7-Oxo-Dehydroepiandrosterone

Series. Steroids 2002;67(3-4):221-233.

Marwah A, Marwah P, Lardy H. Ergosteroids VI: Metabolism of

Dehydroepiandrosterone by Rat Liver in vitro a Liquid Chromatographic-mass

Spectrometric Study. J Chromatogr B Analyt Technol Biomed Life Sci

2002;767(2):285-299.

Marwah A, Marwah P, Lardy H. Development and Validation of a High-Performance

Liquid Chromatography Assay for the Quantitative Determination of 7-Oxo-

Dehydroepiandrosterone-3-Beta-Sulfate in Human Plasma. J Chromatogr B

Biomed Sci Appl 1999;721(2):197-205.

Shi J, Schulze S, Lardy H. The Effect of 7-Oxo DHEA Acetate on Memory in Young

and Old C57BL/6 Mice. Steroids 2000;65(3):124-129.

Gomez FE, Miyazaki M, Kim YC, Marwah P, Lardy H, Ntambi JM. Molecular

Differences Caused by Differentiation of 3T3-L1 Preadipocytes in the Presence

of Either Dehydroepiandrosterone (DHEA) or 7-Oxo DHEA. Biochemistry

2002;41(17);5473-5482.

Lardy H, Henwood SM, Weeks CE. An Acute Ora l Gavage Study of

3-acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA-acetate) in Rats. Biochem and

Biophys Res Comm 1999;254:120-123.

Henwood SM, Weeks CE, Lardy H. An Escalating Dose Oral Gavage Study of

3-acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA-acetate) in Rhesis Monkeys.

Biochem and Biophys Res Comm 1999;254:124-126.

Nelson R. et al., Dehydroepiandrosterone and 7-Keto DHEA Augment Interleukin 2

(IL-2) Production by Human Lymphocytes in Vitro, Presented at 5th Conference on

Retroviruses and Opportunistic Infections 1998, Chicago, IL.

Lardy H, Marwah A, Marwah P. Transformations of DHEA and Its Metabolites

by Rat Liver. Lipids 2002;37(12):1187-1191.

Liu YY, Yang N, Kong LN, Zuo PP. Effects of 7-oxo-DHEA on the Immunoreactivity of

BALB/c Mice Subjected to Chronic Mild Stress. Yao Xue Xue Bao 2003;38(12):881-

884.

Clinical Studies

Davidson M, Marwah A, Sawchuk RJ, Maki K, Marwah P, Weeks C, Lardy H. Safety

and Pharmacokinet ic Study wi th Esca la t ing Doses of 3-acety l-7-

oxo-dehydroepiandrosterone in Healthy Male Volunteers. Clin Invest Med

2000;23:300-310.

Sulcova J, Hill M, Masek Z, Ceska R, Novacek A, Hampl R, Starka L. Effects

of Transdermal Application of 7-Oxo DHEA on the Levels of Steroid Hormones,

Gonadotropins and Lipids in Healthy Men. Physiol Res 2001;50(1):9-18.

Kalman DS, Colker CM, Swain MA, Torina GC, Shi Q. A Randomized, Double-Blind,

Placebo Controlled Study of 3-Acetyl-7-Oxo-Dehydroepiandrosterone in Healthy

Overweight Adults. Current Therapeutic Research 2000;61:435-442.

Zenk JL, Helmer TR, Kassen LJ, Kuskowski MA. The Effect of 7-Keto Naturalean on

Weight Loss: A Randomized, Double-Blind, Placebo-Controlled Trial. Current

Therapeutic Research 2002;63:263-272.

Zenk JL, Kuskowski MA. The Use of 3-acetyl-7-oxo-dehydroepiandrosterone for

Augmenting Immune Response in the Elderly, Abstract Presented at the meeting of

the FASEB, April 17, 2004, Manuscript submitted for publication.

Zenk JL, Leikam SA, Kuskowski MA. A Randomized, Double Blind, Placebo

Contro l led Tr ia l to Invest iga te the Ef fect o f 3-acety l-7-oxo-dehy-

droepi-androsterone in Subjects with Acute or Chronic Active Crohn’s Disease.

Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. A Prospective, Randomized,

Double Blind Study to Evaluate the Effect of Lean System-7 on Body Composition.

Nutrition 2005; 21:179-185.

Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. A Prospective, Randomized,

Double Blind Study to Evaluate the Effect of Lean Source™ on Body Composition

in Overwieght Adult Men and Women. Abstract Presented at the meeting of the

FASEB, April 17, 2004, Manuscript submitted for publication.

Zenk JL, Leikam SA, Kuskowski MA. The Effect of Restricted Calorie Diet and

7-oxo DHEA on Resting Metabolic Rate: An Exploratory, Crossover Study,

Manuscript Pending.

Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. A Prospective, Randomized,

Double Blind Study to Evaluate the Effect of HUM5007 and 7-oxo DHEA on Resting

Metabolic Rate in Overweight Adult Men and Women on a Calorie Restricted Diet.,

Abstract Presented at the meeting of the FASEB, April 17, 2004, Manuscript sub-

mitted for publication.

References for 7-KetoTM

Humanetics CorporationThe Science of Supplements®

12200 Middleset Road, Suite 500Eden Prairie, Minnesota, 55344

Phone: 952-937-7660Fax: 952-937-7667

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