Information summary for healthcare

professionals
Index:

DOXYVA and its positive impact on patients health 1

What is DOXYVA? 1
Who is involved in improving healthcare for patients? 2
What do we usually remember about CO2? 2
What do we usually forget about pCO2? 2
Where does CO2 vapor delivered through the skin take action in the body? 3
When will patients begin to perceive healthcare benefits after starting CO2 therapy with DOXYVA? 4
Why can the DOXYVA medical device and its capacity to produce highly concentrated CO2 vapor
improve general health care? 7
Is DOXYVA safe for my patients (humans and pets)? 8
Circularity-funded research performed by healthcare experts 8
Skin lesions 8
Blood flow (flux) assessments 9
Benefits for doctors 10
Possible risks of and adverse reactions to DOXYVA device and highly concentrated CO2 water vapor: 10
References 11

DOXYVA and its positive impact on patients health

What is DOXYVA?
The DOXYVA device is a simple, commercially- available device to deliver transdermal carbon
dioxide (CO2). It consists of a patented and patent-pending ergonomic polymer shell that is
propelled by a patented single-use mini steel pressurized cartridge (45 psi) filled with
pharmaceutical-grade (99.5%) liquid, purified CO2. The mini-steel cylinder is GMP-compliant,
and recyclable.

DOXYVA was identified by the IRB in a human clinical trial as a non-significant risk (NSR) device.

The DOXYVA device is manufactured in the United States and other countries. DOXYVA is an
ISO-complaint device, which means that Circularity Healthcare, LLC has received a certification
to certify that DOXYVA fulfills all of the international requirements for medical device
regulations, like risk assessment and maintaining effective processes for safe design,
manufacture and distribution.

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Who is involved in improving healthcare for patients?
CO2 is the protagonist in DOXYVAs revolutionary approach to improving healthcare and
patients quality of life. The medical device causes controlled ischemia-like stress in a local area
of the body to promote central nervous system activity and circulate humoral agents that favor
micro-circulation, especially at the organ capillary beds.

Adequate blood flow in the capillary bed is essential for tissue survival and optimal organ
function. If blood passes too fast or does not pass at all, the tissue cannot extract O2 efficiently
and will generate what is known as capillary dysfunction, which is related to chronic pain, poor
wound healing, diabetic neuropathy and Alzheimers disease, among other conditions.

What do we usually remember about CO2?

It is a key player in regulating extracellular hydrogen concentrations and pH through
various systems, like the respiratory system, kidneys and various buffers.
Biochemistry: An increase or decrease in 1 mmHg pCO2 will cause a decrease or
increase in pH of 0.08 units in acute patients. In chronic patients, a pCO2 change of 1
mmHg will cause a pH change of 0.03 units.
The Bohr and Haldane effects determine the interaction of O2 and CO2. At the cellular
level, pCO2 concentration causes Hb-O2 dissociation.
It is attained by our body through inhalation.

What do we usually forget about pCO2?

Increased pCO2 promotes arteriolar dilatation in various tissues, while a modest
effect has been shown in skeletal muscle tissues.
CO2 can be delivered into our body through the skin (transdermal).
It is used in the medical industry to:
Rapidly increase depth of anesthesia when volatile agents are being
administeredit increases the depth of respiration and helps to
overcome breath holding and bronchial spasm
Facilitate blind intubation in anesthetic practice
Facilitate vasodilation and thus lessen the degree of metabolic acidosis
during the induction of hypothermia
Increase cerebral blood flow in arteriosclerotic patients undergoing
surgery
Stimulate respiration after a period of apnea
Prevent hypocapnia during hyperventilation

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 It is also used in:
Clinical and physiological investigations
Gynecological investigations for insufflation into the fallopian tubes and
abdominal cavities
Tissue-freezing techniques (as dry ice) and to destroy warts by freezing.
The CO2 concentration increment potentiates the S-shaped hemoglobin (Hb) to O2
dissociation curve. It helps Hb to unload O2 from 40% O2 dissociation under normal
conditions to 70% O2 dissociation under increase CO2 concentration.

Where does CO2 vapor delivered through the skin take action in the
body?
Transdermal delivery of CO2 has proved to improve local microcirculation (capillary beds) blood
flow and tissue perfusion, but it also positively improves systemic blood pressure and TcpO2
(most likely due to the Bohr effect). As mentioned before, therapeutic medical-grade CO2 is
used for vasodilatation in the medical field for several conditions and procedures.

Local, CO2 therapy has shown great success rates to improve the healthcare of patients
through:
Treatment for diabetic foot
Increased microcirculation blood flow and dissociated O2 in healthy and diabetic
individuals
Treatment for arterial stenosis obliterans
Chronic wound healing
Adipose tissue treatment

Systemically, CO2 therapy has shown great success to improve:

The healthcare of patients with high blood pressure
General vital organ function, like that of the:
- Pancreas
- Liver
- Brain
- Kidneys

We are currently finding clinical researchers who are interested in participating in clinical trials
with our medical device. Our goal is to produce scientific evidence of DOXYVAs potential to
improve healthcare.

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Outstanding clinical research results
More than two dozen research projects have been performed to test DOXYVA potential and its
capability to help patients obtain wellness. We have tested the efficiency, tolerability and safety
of the DOXYVA medical device in delivering a gentle, highly concentrated CO2 mist to the body
through the skin and prove the reproducibility of its effects beyond doubt. To do so, we
measured body CO2 concentration before and after treatment as well as the expected
physiological response to CO2 treatment. In addition, we have partnered with healthcare
leaders and clinicians to perform independent research studies.

Research end points:

1) Safety and tolerability

Up to date, no adverse side effects or negative healthcare responses have
been recorded from our clients using D'OXYVA. Also, no participants in
our research projects had any documented side effects from treatment.
We encourage you to discuss with your healthcare professional if
DOXYVA medical device is right for you.

a. Measured transcutaneous carbon dioxide (TcPCO2)

Within the first 5 minutes of DOXYVA treatment, TcPCO2 increases in the
body, followed by a decline slope that lasts approximately 240 minutes
until returning to baseline values.
In healthy individuals, DOXYVA does not increase pCO2 beyond the body
buffers manageable range, making it completely safe.

2) Efficiency CO2 delivery

a. Measured blood perfusion index (PI)

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 The results of each research project consistently showed a significant
increment on PI in 100% of participants within the first 5 minutes of
treatment, peaking at 60 minutes after treatment. From 60 minutes after
treatment until 240 minutes (our largest time period evaluated after

Graph 1: Skin perfusion index (SPP) in healthy and diabetic participants vs. time
after using the DOXYVA medical device

treatment), PI decreased slowly to baseline levels. PI studies on diabetic

patients has demonstrated a greater response to CO2 that in non-diabetic
healthy individuals. Our studies have recorded that the PI change (from
baseline) in diabetic patients was double the PI change recorded in
healthy patients (Graph 1).

b. O2 concentration
DOXYVA has consistently reported increased free O2 molecules in our
patients blood streams. The effective transdermal CO2 delivery allows
the body to increment O2 availability through the Bohr effect, which
helps hemoglobin cells to unload O2 more easily by decreasing its affinity.

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 c. Blood pressure
All of the research projects performed up to date have consistently
recorded a significant decrease in systolic blood pressure (from the heart)
and diastolic (return to the heart) blood pressure. These results have
been consistent throughout all study time periods up to 240 minutes (our
longest time period evaluated after treatment).

d. Diabetic ulcer
A research project focusing on DOXYVAs impact on diabetic ulcers
recorded significant changes in wound healing, like significant granulation
of tissue and improved ulcer borders, as soon as 1 week into the
DOXYVA treatment plan (Image 1).

Image 1

After 7 days of
treatment with
DOXYVA (1x
per day) same
wound dressing
as before

e. Sports
Amateur and professional athletes are always searching for ways to
improve cardiovascular function and increase the vascular transport
capacity of skeletal muscle. Better vascular transport capacity translates
to more O2 and nutrients delivered to our muscles, which means better
performance in the field.

DOXYVA research focusing on the perfusion index (PI) of superficial

skeletal muscles has recorded excellent results. The most important
findings demonstrate that participants who use DOXYVA doubled their PI
in comparison to the control group.

f. Blood alkalinity
Use of DOXYVA has consistently been shown to improve local cellular
homeostasis. It has the potential to improve body pH values by
promoting an alkaline ambiance. A slightly alkaline microenvironment

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 within the body promotes good health and optimal body organ
performance.

When will patients begin to perceive healthcare benefits after starting

DOXYVA?
The SENTEC digital monitor system has confirmed successful and constant CO2 transdermal
delivery to the skin capillary bed after a 5-minute period of exposure to highly concentrated
CO2 vapor produced by DOXYVA.

The perceived healthcare benefits occur almost instantly, with local microcirculation
improvements followed by an increment of SPO2 that last up to 240 minutes.

Nonetheless, adherence to a DOXYVA regiment has demonstrated benefits to individuals

suffering from difficult-to-heal skin wounds like diabetic ulcers, who demonstrated significant
clinical improvements after two weeks of DOXYVA.

Patients who achieved DOXYVA device adherence for more than a month have shown wellness
that persists in clinical trials.

Why can the DOXYVA medical device and its capacity to produce highly
concentrated CO2 vapor improve general health care?
Judy M. Delp, Ph.D. in physiology and professor at the Florida State University, described
DOXYVA as a simple commercially available device used to deliver transdermal CO2 that has
shown remote vasodilation, which may be mediated through the release of a circulating
humoral agent.**

CO2 improves general healthcare in several ways:

It has natural anti-inflammatory characteristics.

It increases blood flow through microcirculation, by arteriolar/venous dilatation.
It produces a rightward shift in the O2 dissociation curve.
It enhances oxygen delivery at the cellular level in the muscles, organs, brain, skin and
other parts of the body.
It is a fat-dissolving compound.
It naturally sedates and calms the central nervous system.
It can be used to reconstruct functionally closed capillaries.
It can improve venous response.

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 It improves blood-flow properties.
It can be used to sedate the central nervous system.

Is DOXYVA safe for my patients (humans and pets)?

Circularity Healthcare operates a state-of-the-art supply chain and quality management system
(QMS) for manufacturing. Circularity has certificates of registration for IS EN ISO13485:2012
(European Union) and ISO13485:2003 under CMDCAS (Canada), which it has been
implementing since 2013.

D'OXYVA is a CE-marked medical device (Class I, low risk) for delivery of medications via the
skin. Circularity is seeking approval from the U.S. FDA and other countries for delivery of
medical gases such as medical carbon dioxide (USP UN1013) via a novel, patented, non-invasive
transdermal route with D'OXYVA to treat various widespread conditions.

Medical carbon dioxide is manufactured and delivered under applicable standards per each
country's regulatory requirements. In the United States, the Food and Drug Administration has
cleared the use of medical carbon dioxide through inhalation for humans but not yet through
transdermal delivery with D'OXYVA. Transportation of medical carbon dioxide via any postal or
courier service requires a certification for handling dangerous goods (HAZMAT) by the U.S.
Department of Transportation (DOT).

Circularity-funded research performed by healthcare experts

Skin lesions:
Title: New prospect of treatment of wound healing

Researcher: Professor Puruhito

o Thoracic, cardiac and vascular surgery, medical faculty, Universitas Airlangga, Surabaya,
Indonesia
Sample: Diabetic patients with ulcers identified as Wagner 1 to 3.

Most important findings:

All diabetic foot ulcers evaluated during the study time period presented marked clinical
improvements, and some patients gained total ulcer resolution.

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Title: Complex treatment of complicated crural decollement injury in a diabetic patient

Researchers: I. Grgyn, . Csonka, K. Boa, E. Varga

o Department of Traumatology, University of Szeged, Hungary
Sample: Case presentation

Most important findings:

A patient had a stage 4 ulcer with necrotic borders secondary to a car-accident-associated

fracture with massive soft tissue contusion and crural decollement. Results: The physician used
the DOXYVA medical device as adjuvant therapy to save the patients limb from amputation and
obtain complete ulcer resolution after 3 months of therapy.

Blood flow (flux) assessments:

Title: Transdermal delivery of carbon dioxide boosts microcirculation in subjects with and
without diabetes

Researchers: Lee C. Rogers, D.P.M., Judy M. Muller-Delp, Ph.D., Topy A. Mudde, MSc.

Sample: Healthy and diabetic patients

Most important findings:

All of the flux parameters demonstrated marked improvement after the use of the DOXYVA
device. The skin perfusion index increased after CO2 transdermal treatment. The diabetic
participants demonstrated the most flux improvement after treatment, compared with healthy
individuals. Both groups demonstrated improved blood pressure.

Title: Pilot study of DOXYVA transdermal gas delivery device in adult equines

Researchers: Dr. Karen Indreland, DVM

Sample: Healthy horses

Most important findings:

A D'OXYVA device was used to provide high-concentration-CO2 water vapor, which increased
microcirculation (flux) blood flow in the superficial skeletal muscle and skin of equines,
compared with the control group.

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Benefits for doctors

1. Be confident in working with a well-proven modality and with a company that is

constantly providing scientific, evidence-based information of DOXYVAs impact on
healthcare and safety.
2. Obtain above-average results in some of the biggest problem areas among our sick
population (cardiovascular problems, diabetes, etc.) with no side effects.
3. The therapy is cost effective and highly effective.
4. The treatment is safe.
5. Distinguish yourself as a professional who is able complement traditional medicine with
an alternative approach that will help you to deliver the results that your patients
expect.
6. Gain more income from more frequent visits for weekly sections.
7. Become a holistic healthcare professional focused on improving quality of life.
8. It is easy to demonstrate and prove the devices ability and credibility.
9. Diversify your patient profile and markets to aesthetics and performance enhancement
for athletes, among others.

Possible risks of and adverse reactions to the DOXYVA device and water
vapor with high CO2 concentration (not yet recorded):
Hypersensitivity
Hypercapnia
Transient hypotension FZ
Orthostatic intolerance
Facial flushing

Until our research community performs further studies, we do not recommend the use of
the DOXYVA medical device for:

Severe hypertension
New cardiac infarctions
Aortic and mitral valve stenosis
Severe congenital heart failure
Cor pulmonale

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 Bronchopulmonary diseases accompanied by hypercapnia
Acute inflammatory vascular diseases

Want to know more about how DOXYVA can help your patients to achieve good health? Want
to talk with a DOXYVA representative and healthcare professional?

www.doxyva.com

References

CELLULITE AND CARBON DIOXIDE BATH. (2009, may 9).

Evaluation of a Novel Medical Device (Carbothera) in the Prevention of Foot Ulcers in Patients With
Critical Limb Ischemia and Undergoing Hemodialysis. (2014). Evaluation of a Novel Medical
Device (Carbothera) in the Prevention of Foot Ulcers in Patients With Critical Limb Ischemia and
Undergoing Hemodialysis.

Chester A. Ray, P. (2013). PENN STATE, D'OXYVA STUDY-- PRELIMINAR RESULTS. The Effect of
Transdermal CO2 Diffusion on Sympathetic Nerve Activity and Vascular Responses in Humans.
PENDING.

Dogaru Gabriela, R. A. (2015). THERAPEUTIC EFFECTS OF CARBONATED MINERAL WATERS IN

CARDIOVASCULAR REHABILITATION . Balneo Research Journal, 36- 39.

HRV. (2016). HRV STUDY TAIWAN . HRV STUDY TAIWAN POWER POINT INFORMATION . TAIWAN .

I. Grgyn, . C. (2016). Complex treatment of complicated crural decollement injury in a diabetic

patient.

Lee C. Rogers, J. M. (2015). Transdermal delivery of Carbon Dioxide Boosts icrocirculation in subjects with
and without diabetes.

Maria Vitria Carmo PenhavelI, V. H. (2013). Effects of carbon dioxide therapy on the healing of acute
skin wounds induced on the back of rats1. Acta Cirrgica Brasileira , 334- 339.

Mitsubishi-Rayon-Cleansui. (2014). Evaluation of a Novel Medical Device (Carbothera) in the Prevention

of Foot Ulcers in Patients With Critical Limb Ischemia and Undergoing Hemodialysis . University
of Manitoba : ClinicalTrials.gov Identifier: NCT02239419.

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Norbert Kiss1, J. M.-D. (2016). LEE ROGERS STUDY JOURNAL . Transdermal Delivery of Carbon Dioxide
Boosts Microcirculation in Subjects with and without Diabetes .

Nouvong, J. S. (n.d.). Assessment of Microcirculation and the Prediction of Healing in Diabetic Foot
Ulcers . Western University of Health Sciences, College of Podiatric Medicine United States of
America: www.intechopen.com.

Puruhito, D. (2015). Professor Puruhito guest speaker at the International Wound Care and Biotherapy
Conference in Kuala Lumpur. (D. P. Kirkitelos, Interviewer)

Schmidt, K. (n.d.). Carbon Dioxide Bath (Carbon Dioxide Spring). Bad Nauheim, Germany: Center for
Clinical Research in Rheumatology, Physical Medicine and Balneotherapy;.

(n.d.). Treatment of Spider Telangiectasias Current Status and a New Trend. Taipei, Taiwan.

V. VARLARO, G. M. (2007). Carboxytherapy:effects on microcirculation and its use in the treatment of

severe lymphedema A review. ACTAPHLEBOL, 1- 8.

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