U.S. patent application number 14/222744 was filed with the patent office on 2015-09-24 for optimal remote ischemic preconditioning (orip) for mitigating dna damage.
This patent application is currently assigned to NEOCARDIUM, LIMITED. The applicant listed for this patent is Fazal Raheman. Invention is credited to Fazal Raheman.
Application Number | 20150265286 14/222744 |
Document ID | / |
Family ID | 44657267 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150265286 |
Kind Code |
A1 |
Raheman; Fazal |
September 24, 2015 |
Optimal Remote Ischemic Preconditioning (ORIP) for mitigating DNA
damage
Abstract
DNA damage commonly results from exposure to diagnostic and
therapeutic use of ionizing radiation, chemotoxic agents, smoking,
diet and even from sedentary lifestyle. It is also a function of
aging. Unrepaired DNA damage may result in accelerated aging and
various forms of cancers. The invention discloses a method to
harness the innate power of repetitive transient ischemia and
reperfusion for protecting organs against imminent DNA damage,
prevent senescence (aging) and for boosting DNA repair. This method
of optimal remote ischemic preconditioning (ORIP) comprises of
utilizing a pair of programmable pneumatic cuffs that
inflate/deflate alternately occluding blood circulation to each of
the limbs for pre-defined time intervals. ORIP can be
self-administered and remotely monitored by clinician. ORIP may
also be deployed as an adjunct in radiotherapy and chemotherapy for
reducing the damage to normal tissue and boosting the treatment
efficacy. The apparatus delivers maximal ORIP dose in shortest
possible time.
Inventors: |
Raheman; Fazal; (Dubai,
AE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Raheman; Fazal |
Dubai |
|
AE |
|
|
Assignee: |
NEOCARDIUM, LIMITED
St Leonard on Sea
GB
|
Family ID: |
44657267 |
Appl. No.: |
14/222744 |
Filed: |
March 24, 2014 |
Current U.S.
Class: |
606/202 |
Current CPC
Class: |
A61B 5/022 20130101;
A61B 5/412 20130101; A61B 2017/00199 20130101; A61B 2017/00221
20130101; A61B 5/413 20130101; A61B 17/1355 20130101 |
International
Class: |
A61B 17/135 20060101
A61B017/135 |
Claims
1. A method of preventing, treating or mitigating the impact of DNA
damage to a healthy human tissue comprising of releasing ischemia
triggered cellular modulators (ITCMs) by means of non-invasively
inducing transient, repetitive and alternate cycles of ischemia and
reperfusion, each lasting not less than 1 minute and not more than
10 minutes, in one or more remote organs, in one or more sessions,
thereby increasing the tissue injury threshold for DNA breaks,
promoting apoptosis of damaged cell, preventing senescence of
damaged cell, and accelerating the process of DNA repair.
2. A method of claim 1, wherein the DNA damage is caused as a
result of an exposure to ionizing radiation during a therapeutic or
diagnostic medical procedure.
3. A method of claim 1, wherein the DNA damage is caused as a
result of exposure to chemotoxic agents.
4. A method of claim 1, wherein the DNA damage is caused as a
result of oxidative stress resulting from lifestyle related causes
or aging.
5. A method of claim 1, wherein DNA damage to the healthy human
tissue is as a consequence of either radiotherapy or chemotherapy
or combination thereof in practice of oncology.
6. A method of claim 1, wherein the treatment is administered as an
adjunct to radiotherapy or chemotherapy, or combination thereof to
enhance the overall efficacy of treatment and reduce the impact of
side effects, the treatment comprising the steps of: a) providing
an acute phase consisting of one or more sessions minutes or hours
prior to the administration of chemotherapy or radiotherapy
regimen, wherein the session comprising of not less than 2 and not
more than 5 ischemic phases per limb, and not less than 2 and not
more than 5 reperfusion phases per limb, each of the ischemia and
reperfusion phases comprising of not less than 1 minute and not
more than 10 minutes of ischemia and reperfusion respectively; and
b) providing a sub-acute phase ORIP treatment regimen initiated not
earlier than the third day subsequent to the administration of a
chemotherapy or radiotherapy regimen, and continuing until at least
8-12 weeks post-procedure, such regimen comprising of not less than
2 sessions per week and not more than 14 sessions per week, and
each session comprising of not less than 2 and not more than 5
ischemic phases per limb, and not less than 2 and not more than 5
reperfusion phases per limb, each of the ischemic and reperfusion
phases comprising of not less than 1 minute and not more than 10
minutes of alternating ischemia and reperfusion cycles
respectively.
7. The method of claim 1, wherein: a) at least one of the remote
organs comprises an upper arm or a wrist, wherein the highest
occlusion pressure is set to not less than 10% and not more than
30% higher than the highest systolic blood pressure measured in the
corresponding upper limb, or not more than 200 mm Hg when the
systolic upper limb pressure is not measured by the device; or a)
at least one of the remote organs comprises a lower limb like a
thigh in which case the highest occlusion pressure is set to not
less than 10% and not more than 30% higher than the highest
systolic blood pressure measured in the corresponding thigh, or not
more than 210 mm Hg when the systolic thigh pressure is not
measured by the device; or b) the remote organs comprise a
combination of the upper and the lower limbs thereof at their
corresponding occlusion pressures respectively.
8. A method of claim 1, wherein a treatment regimen involves at
least a pair of remote organs that includes a first limb and a
second contralateral limb attached to an optimal remote ischemic
preconditioning (ORIP) apparatus comprising the steps of: a)
providing a pair of auto-inflatable pneumatic cuffs, attaching a
first cuff to the first limb and a second cuff to the second limb,
wherein one of the cuffs inflates significantly beyond systolic
blood pressure to completely occlude the blood flow in ischemic
phase, and deflate one of the contralateral paired cuffs to allow
free flow of blood in the contralateral limb in reperfusion phase,
wherein inflation and deflation in the paired cuffs is done in
cycles that alternate with similar but opposite
ischemia-reperfusion cycles of the paired cuff attached to the
patient's remote organ resulting in systemic release of optimal
levels of therapeutic ITCMs, b) providing an air pumping module
with a single or paired air pump, an inflate and a deflate valve
for each of the paired cuffs, which pump air to each cuff through a
tube and holds air in the ischemic phase at a cuff pressure
significantly beyond the systolic blood pressure for occluding the
blood flow to the patient's first remote organ for a predefined
time, and releases the air in the reperfusion phase allowing the
blood to flow freely, thereby when the first organ is in ischemic
phase the second organ is in reperfusion phase, resulting
accomplishing twice the ischemic body area for the release of the
therapeutic ITCMs in half the time required by a single cuff
ischemic preconditioning procedure and thus providing a more potent
protection against DNA breaks and boost DNA repair without causing
significant patient discomfort, c) providing a pressure transducer
module for measuring the minimal blood flow occlusion pressure to
set up the maximal occlusion pressure in the ischemic phase for
each of the paired cuffs, wherein the transducer is selected from
the group consisting of: an oscillometric transducer, a
photoplethysmographic transducer, an ultrasonic transducer, a
thermal transducer, or an infrared transducer, d) providing a
controller console housing which has mechanical and electronic
components that automatically operate both the paired cuffs, the
air pumping module, the transducers, a user interface and a
microprocessor that is programmable to automatically inflate and
deflate the pneumatic cuffs alternatively to predefined cuff
pressure levels, in predefined repetitive cycles, and in predefined
order of each of the two remote organs, wherein the controller
console displays the ORIP treatment protocol and the status in a
real time graphic user interface for user interaction with the
microprocessor and other electronic components that are stored in
the microprocessor selected from a group consisting of: selection
and initiation of a particular ORIP session in compliance with
clinician's prescription, calling for a readout of some previously
stored data, or setting into the microprocessor patient related
data, times and dates relating to specific ORIP sessions and
regimen, and also providing user with means to switch the device on
or off, and e) providing a wired or wireless communication module
to receive and send feeds from and to a clinician regarding the
compliance to a clinician-prescribed ORIP treatment regimen, to
alter the ORIP treatment regimen, or to prescribe a new ORIP
treatment regimen, wherein the wireless communication module is
selected from a group consisting of WIFI, GPRS, TCP/IP or peer to
peer RF transmission through an RF-enabled handheld communication
device in the vicinity of the ORIP console.
9. A method of preventing, treating or mitigating the impact of DNA
damage to a healthy human tissue comprising of releasing ischemia
triggered cellular modulators (ITCMs) by means of non-invasively
inducing transient, repetitive and alternate cycles of ischemia and
reperfusion in a pair of remote organs including a first limb and a
second contralateral limb attached to an optimal remote ischemic
preconditioning (ORIP) apparatus comprising the steps of: a)
providing a pair of auto-inflatable pneumatic cuffs, attaching a
first cuff to the first limb and a second cuff to the second limb,
wherein one of the cuffs inflates significantly beyond systolic
blood pressure to completely occlude the blood flow in ischemic
phase, and deflate one of the contralateral paired cuffs to allow
free flow of blood in the contralateral limb in reperfusion phase,
wherein inflation and deflation in the paired cuffs is done in
cycles that alternate with similar but opposite
ischemia-reperfusion cycles of the paired cuff attached to the
patient's remote organ resulting in systemic release of optimal
levels of therapeutic ITCMs, b) providing an air pumping module
with a single or paired air pump, an inflate and a deflate valve
for each of the paired cuffs, which pump air to each cuff through a
tube and holds air in the ischemic phase at a cuff pressure
significantly beyond the systolic blood pressure for occluding the
blood flow to the patient's first remote organ for a predefined
time, and releases the air in the reperfusion phase allowing the
blood to flow freely, thereby when the first organ is in ischemic
phase the second organ is in reperfusion phase, resulting
accomplishing twice the ischemic body area for the release of the
therapeutic ITCMs in half the time required by a single cuff
ischemic preconditioning procedure and thus providing a more potent
protection against DNA breaks and boost DNA repair without causing
significant patient discomfort, c) providing a pressure transducer
module for measuring the minimal blood flow occlusion pressure to
set up the maximal occlusion pressure in the ischemic phase for
each of the paired cuffs, wherein the transducer is selected from
the group consisting of: an oscillometric transducer, a
photoplethysmographic transducer, an ultrasonic transducer, a
thermal transducer, or an infrared transducer, d) providing a
controller console housing which has mechanical and electronic
components that automatically operate both the paired cuffs, the
air pumping module, the transducers, a user interface and a
microprocessor that is programmable to automatically inflate and
deflate the pneumatic cuffs alternatively to predefined cuff
pressure levels, in predefined repetitive cycles, and in predefined
order of each of the two remote organs, wherein the controller
console displays the ORIP treatment protocol and the status in a
real time graphic user interface for user interaction with the
microprocessor and other electronic components that are stored in
the microprocessor selected from a group consisting of: selection
and initiation of a particular ORIP session in compliance with
clinician's prescription, calling for a readout of some previously
stored data, or setting into the microprocessor patient related
data, times and dates relating to specific ORIP sessions and
regimen, and also providing user with means to switch the device on
or off, and e) providing a wired or wireless communication module
to receive and send feeds from and to a clinician regarding the
compliance to a clinician-prescribed ORIP treatment regimen, to
alter the ORIP treatment regimen, or to prescribe a new ORIP
treatment regimen, wherein the wireless communication module is
selected from a group consisting of WIFI, GPRS, TCP/IP or peer to
peer RF transmission through an RF-enabled handheld communication
device in the vicinity of the ORIP console.
10. A method of claim 9, wherein the DNA damage is caused as a
result of an exposure to ionizing radiation during a therapeutic or
diagnostic medical procedure.
11. A method of claim 9, wherein the DNA damage is caused as a
result of exposure to chemotoxic agents.
12. A method of claim 9, wherein the DNA damage is caused as a
result of oxidative stress resulting from lifestyle related causes
or aging.
13. A method of claim 9, wherein DNA damage to the healthy human
tissue is as a consequence of either diagnostic radiation exposure,
radiotherapy or chemotherapy or combination thereof in practice of
oncology.
14. A method of claim 9, wherein the treatment is administered as
an adjunct to radiotherapy or chemotherapy, or combination thereof
to enhance the overall efficacy of treatment and reduce the impact
of side effects, the treatment comprising the steps of: a)
providing an acute phase ORIP treatment consisting of one or more
sessions minutes or hours prior to the administration of
chemotherapy or radiotherapy regimen, wherein the session
comprising of not less than 2 and not more than 5 ischemic phases
per limb, and not less than 2 and not more than 5 reperfusion
phases per limb, each of the ischemia and reperfusion phases
comprising of not less than 1 minute and not more than 10 minutes
of ischemia and reperfusion respectively; and b) providing a
sub-acute phase ORIP treatment regimen initiated not earlier than
the third day subsequent to the administration of a chemotherapy or
radiotherapy regimen, and continuing until at least 8-12 weeks
post-procedure, such regimen comprising of not less than 2 sessions
per week and not more than 14 sessions per week, and each session
comprising of not less than 2 and not more than 5 ischemic phases
per limb, and not less than 2 and not more than 5 reperfusion
phases per limb, each of the ischemic and reperfusion phases
comprising of not less than 1 minute and not more than 10 minutes
of alternating ischemia and reperfusion cycles respectively.
15. The method of claim 9, wherein: a) at least one of the remote
organs comprises an upper arm or a wrist, wherein the highest
occlusion pressure is set to not less than 10% and not more than
30% higher than the highest systolic blood pressure measured in the
corresponding upper limb, or not more than 200 mm Hg when the
systolic upper limb pressure is not measured by the device; or b)
at least one of the remote organs comprises a lower limb like a
thigh in which case the highest occlusion pressure is set to not
less than 10% and not more than 30% higher than the highest
systolic blood pressure measured in the corresponding thigh, or not
more than 210 mm Hg when the systolic thigh pressure is not
measured by the device; or c) the remote organs comprise a
combination of the upper and the lower limbs thereof at their
corresponding occlusion pressures respectively.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part (CIP) of U.S.
patent application Ser. No. 12/898,259 filed Oct. 5, 2010, which
claimed the benefit of U.S. Provisional Application No. 61/317,294
filed Mar. 25, 2010. These above referenced applications are herein
incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
REFERENCE TO A MICROFICHE APPENDIX
[0003] Not Applicable
FIELD OF THE INVENTION
[0004] The present invention relates generally to transiently and
repeatedly auto inflating pneumatic cuffs for inducing limb
ischemia distal to its site of occlusion and preconditioning the
entire human body to subsequent ischemic and other physiological
and pathological insults. More particularly it is a method of
remote ischemic preconditioning by occluding limb circulation
utilizing a pair of pneumatic cuffs that inflate and deflate
alternately for a pre-specified time to induce optimal limb
ischemia sufficient for inducing system-wide ischemic
preconditioning for protecting the organs from DNA damage resulting
from physiological, pathological, radiological, chemical insults or
merely as result of aging.
BACKGROUND OF THE INVENTION
[0005] There are numerous references mentioned in the parent
application incorporated by reference herein which provide
background information of the invention, and which themselves are
incorporated by reference herein.
[0006] Background information about the embodiments of the
invention claimed herein is found in particular in the Ser. No.
12/898,259 application. Definitions of terms used in the instant
application are also set forth in the '259 application.
[0007] Preferred embodiments of the present invention are described
below and unless specifically noted, it is the applicant's
intention that the words and phrases in the specification and
claims be given the ordinary and accustomed meaning to those of
ordinary skill in the applicable art(s). Likewise, it is
applicant's intention to cover and include any and all structure,
materials or acts that perform the claimed function, along with any
and all known or later developed equivalent structures, materials
or acts for performing the claimed function.
[0008] Optimal Remote Ischemic Preconditioning (ORIP) is a
non-invasive medical device that induces systemic production of
ischemia triggered cellular modulators (ITCMs) by means of causing
repetitive and intermittent ischemia and reperfusion in a remote
organ such as upper or lower limbs. A large body of peer-reviewed
literature establishes that such ITCMs, prominent among them being
NF-Kappa B inhibitors, are released in circulation and reach the
target organs to protect them against impending stress or injuries
including DNA damage. These cellular modulators increase the
threshold of the tissue to tolerate biological insults anywhere in
the body. ORIP therefore is a very broad platform technology that
has applications in a wide range of health conditions.
[0009] In the parent application '259, applicant disclosed
following six broad categories of ORIP treatment regimens for
preventing organs from eminent pathophysiological insults:
1. EMS (Emergency Medical Services): [0081]
2. P3 (Pre-Procedure Preconditioning): [0082]
3. CC (Critical Care): [0083]
4. CMS (Chronic Medical Service. [0085]
5. Coronary Revascularization Adjunct: [0086]
6. Heart Repair Adjunct [0088]
[0010] A very important category of biological insult that results
from our modern lifestyle is the damage caused to our DNA as a
result of exposure to ionizing radiations, chemicals, smoking,
diet, lack of exercise, and even as a result of normal aging
process. DNA damaged cells if left unrepaired may either age faster
or become cancerous.
[0011] As disclosed in '259 ORIP can be deployed as a
"pre-procedure preparation (P3) device prior to an elective
intervention such as, coronary bypass surgery, coronary
angioplasty, vascular surgery, organ transplant so on and so
forth." In medical practice, particularly in practice of oncology
and radiology, a substantial number of elective interventions
result in unwanted DNA damage as a result of such diagnostic or
therapeutic procedures. Increased DNA damage also results from
unhealthy lifestyle that includes but not limited to environmental
and medical exposure to ionizing radiation, oxidative stress due to
chemotoxic agents, smoking, diet, lack of exercise and even normal
aging process. Very recently a research group reported DNA damage
resulting from third hand smoke and potential cancer (Bo Hang.
American Chemical Society, Mar. 14, 2014). Increased DNA damage not
only cause cancers, but also accelerates the aging process.
Ionizing Radiation Related DNA Damage
[0012] Diagnostic x-rays are the largest man-made source of
radiation exposure, and interventional radiologic procedures differ
from other x-ray-exposing procedures in terms of a variety of
parameters. As compared with plain-film radiography, CT involves
much higher doses of radiation, resulting in a marked increase in
radiation exposure in the population. CT accounts for 15% of all
procedures in radiology but contributes 50% of the population dose
resulting from the diagnostic use of ionising radiation. The
widespread use of CT represents probably the single most important
advance in diagnostic radiology.
[0013] Preceding decades have seen a continuous increase in the
frequency of diagnostic and interventional cardiac procedures. It
is paramount that radiation protection in such procedures must be a
matter of primary concern. In addition to this the patients are
becoming increasingly aware and concerned about radiation hazards
acquired during interventional procedures. As we know that the
effects of radiation exposure are not apparent immediately but
long-term consequences can be serious, Ionizing radiation is a
hazard that cannot be detected by the human senses.
[0014] Non-invasive imaging technologies continue to revolutionize
every subspecialty of medicine. Multi-slice CT delivers increased
levels of focused radiation compared with single slice CT. Clinical
use of multi-slice CT is increasing and the 64-slice cardiac CT
heralds the new age of non-invasive cardiac imaging. Nevertheless,
despite the promise of 64-slice CT in non-invasive cardiac
diagnostics, there are serious concerns in their widespread use
because of very high levels of radiation exposure. Median estimated
radiation dose for cardiac computed tomography angiography is
equivalent to 12 mSv, which is comparable with 1.2 times the dose
of an abdominal CT, more than twice that of invasive coronary
angiography or 600 chest radiographs. Such high radiation exposure
does enhance the risk of cancer substantially.
[0015] A study estimating diagnostic X-Ray related risk of cancer
in developed countries found that the attributable risk ranged from
0.6% to 1.8% except in Japan, which was more than 3% (Berrington de
Gonzalez A, Darby S. Risk of cancer from diagnostic X-rays:
estimates for the UK and 14 other countries. Lancet. 2004 Jan. 31;
363(9406):345-51). In US it was estimated that 29,000 new cancers
resulted from 72 million CT scans in 2007 (Berrington de Gonzalez,
A et al. Projected Cancer Risks From Computed Tomographic Scans
Performed in the United States in 2007. Arch Intern Med. 2009;
169(22):2071-2077). It is estimated that 1 in 270 women who
underwent CT coronary angiography at age 40 years will develop
cancer from that CT scan, as against 1 in 600 men. Despite these
caveats, the technology is a major advance and continues to be
refined. Prototypes for 128-slice and even 256-slice scanners are
aggressively developed. However, the small risk of cancer from
radiation exposure to multi-slice CT scanners is limiting the
utility of this highly effective innovation in imaging. If this
risk is eliminated the risk-benefit analysis will favor the use of
this revolutionary technology in screening the general population
that is at risk of coronary artery disease.
[0016] Approximately 150 million scans can be attributed to US,
Europe and Japan annually. Thus a substantial majority of
population at risk of cardiovascular and life style diseases would
immensely benefit if an approach was available to make these high
resolution CT imaging procedures safer with reduced damage to DNA
and reduced life-term risk for cancers.
[0017] Apart from diagnostic radiation exposure, therapeutic use of
radiotherapy, chemotherapy and a combination thereof is also a
major cause of collateral DNA damage to the normal healthy cells.
If such collateral DNA damage to healthy cells is checked, the
practice of oncology will greatly improve in terms of cancer
treatment.
[0018] Nuclear factor Kappa B (NF-KappaB) is activated as part of
the DNA damage response induced by ionizing radiation. NF-Kappa B
triggers inflammatory and cell survival pathways that promote
mutations, senescence and eventual carcinogenic transformation of
the DNA-damaged cells. It down-regulates apoptosis, thereby
promoting survival of cells with damaged DNA that serve as
precursors of cancer. NF-Kappa B activity also down-regulates the
DNA repair Ku protein and p53 expression resulting in more DNA
damage.
[0019] NF-Kappa B regulates over 300 genes involved in cellular
injury/stress, inflammation and repair cycle. Xuan et al were
amongst the first to report that NF-Kappa B is involved in remote
ischemic preconditioning (Xuan Y T, Tang X L, Banerjee S, et al:
Nuclear factor-kB plays an essential role in the late phase of
ischemic preconditioning in conscious rabbits. Circ Res 1999;
84:1095-1109). Remote ischemic preconditioning is known to reduce
the expression of NF-kappa B, TNF-alpha, IL-1beta, and ICAM-1.
Activation of NF-Kappa B is a key event in brain injury and
tolerance can be induced by remote ischemic preconditioning
(Steiger H J, Hanggi D. Ischaemic preconditioning of the brain,
mechanisms and applications. Acta Neurochir (Wien). 2007 January;
149(1):1-10. Epub 2006 Dec. 14.).
[0020] Remote ischemic preconditioning modifies gene expression by
regulating protective genes via the NF-Kappa B activity modulation
(Saxena P et al. Remote Ischemic Conditioning: Evolution of the
Concept, Mechanisms, and Clinical Application. J Card Surg 2010;
25; 127-134). Changes in gene expression occur in both early and
delayed phases of remote preconditioning. Remote ischemic
preconditioning can regulate NF-KB via multiple pathways including
innate immunity pathways and a ubiquitous phosphoinositide-3 kinase
(PI3K) pathway. The ability of remote ischemic preconditioning to
modulate NF-Kappa B pathway has been hailed as Holy Grail and a
road to an amazing discovery (Konstantinov E and Redington, A N.
Linking gene expression, nuclear factor kappa B, remote ischemic
preconditioning, and transplantation: A quest for an elusive Holy
Grail or a road to an amazing discovery? J. Thorac. Cardiovasc.
Surg., 2006; 131(2): 507-509.)
[0021] Currently there is no product that satisfies this
substantial and urgent unmet need to mitigate the effects of
ionizing radiation exposure or countering the rigors of oxidative
stress. ORIP technology provides an approach to minimize the
radiation or oxidative stress induced DNA damage and consequently
eliminates or minimizes the risk for consequential cancers and cell
senescence. ORIP treatment regimen of instant invention can be
administered to a patient in one or more sessions prior to exposure
to a high radiation diagnostic or therapeutic procedure and as
required thereafter to minimize DNA damage, radio-toxicity and
resultant cancer risk.
Oxidative DNA Damage
[0022] Free radicals and other reactive species are constantly
generated in vivo and cause oxidative damage to DNA at a rate that
is probably a significant contributor to the age-related
development of cancer. Oxidative DNA damage is an inevitable
consequence of cellular metabolism, with a propensity for increased
levels following toxic insult. (Cooke et al. Oxidative DNA damage:
mechanisms, mutation, and disease. FASEB J. 2003 July;
17(10):1195-214). Research suggests that oxidative DNA damage is
induced in lung DNA by cigarette smoking. Even third-hand smoke has
be implicated in DNA damage and potential cancer (Bo Hang. American
Chemical Society, Mar. 14, 2014). Oxidative stress and DNA damage
has also been shown to result from high fat and high calorie diets.
Mutations caused by oxidative DNA damage contribute to many human
diseases. Therefore oxidative DNA damage is a "biomarker" for
identifying persons at risk (for lifestyle or genetic reasons, or
both) of developing cancer and for suggesting how the lifestyles of
these persons could be modified to decrease that risk. Measures
that decrease oxidative DNA damage should thus decrease the risk of
cancer development. As discussed earlier Optimal Remote Ischemic
Preconditioning inhibits the NF-Kappa b activation and therefore
plays a crucial role in preventing or mitigating the impact of DNA
damage resulting from all kinds of oxidative stress.
DNA Repair
[0023] DNA damage usually results in repair within hours of the DNA
damaging insult. If repair fails, either apoptosis (programmed cell
death) ensues, or unregulated cell division eventually results in
malignancy. In high-risk individuals or in those with DNA repair
disorders these biological insults may result in cumulative DNA
damage that cannot be repaired by their overburdened DNA repair
mechanisms. Several reports establish that ischemic preconditioning
directly triggers several DNA repair pathways and modulators,
thereby enhancing the repair of endogenous oxidative DNA damage,
which would result in lowering the cumulative burden of damaged DNA
in individuals who are already overwhelmed because of the defective
DNA repair system.
[0024] Cellular response to DNA damage is complex and relies on the
simultaneous activation of different networks. It involves DNA
damage recognition, repair, and induction of signaling cascades
leading to cell cycle determining responses. If the rate of DNA
damage exceeds the capacity of the cell to repair it, the
accumulation of errors can overwhelm the cell and result in early
senescence, apoptosis or cancer. The fate of damaged cells depends
on the balance between pro- and anti-apoptotic signals. In this
decisive life or death choice, the transcription factor NF-kappa B
has emerged as a pro-survival actor in most cell types,
consequently associated with tumorigenic process as it protects
cancerous cells from programed death. NF-Kappa B activity
down-regulates the DNA repair Ku protein and p53 expression.
[0025] Besides down-regulating NF-Kappa B, remote ischemic
preconditioning triggers a cascade of ischemia cellular modulators
(ITCMs), some of which may supplement the impaired DNA repair
pathways. Such ITCSMs include sirtuin (SIRT1)--the longevity
protein, now known to perform additional function of DNA repair.
Similarly p53, primarily a cancer suppressor gene inversely
modulated by NF-Kappa B activity, is also known to perform DNA
repair functions.
[0026] Considering countless number of sources of DNA damage that
humanity faces on daily basis, there's no known intervention that
can prevent or minimize DNA damage, accelerate DNA repair, stop
mutations in damaged DNA, facilitate apoptosis of irreparable DNA,
and prevent early senescence of the healthy cells. Therefore there
is urgent need to solve these problems and accomplish the entire
procedure of prescribing, administering, monitoring and measuring
and optimizing the ischemic preconditioning regimen with a single
touch user-friendly device requiring very little of the physician
time or with his remote supervision of the treatment protocol.
SUMMARY OF THE INVENTION
[0027] The present invention addresses the foregoing need for a
method and apparatus for prescribing, administering and monitoring
optimal remote ischemic preconditioning for the purpose of
preventing DNA damage to organs as a result of routine biological
or physiological insults. Accordingly, there is a need for a
versatile invention as summarized herein in some detail.
Consequently, it is an advantage of the invention that it
objectively administers the prescribed remote ischemic
preconditioning dose optimally with a single touch and in half the
time of any manual or automatic procedure known to the prior art,
without significant pain or discomfort to the patient. It is
further advantage of the method that it creates at least two
ischemic-reperfusion zones in two different remote organs of the
patient in a single dosing session thereby creating a much larger
ischemic preconditioning space resulting in a much stronger
protective response to ongoing or impending DNA damage.
[0028] It is therefore an object of the present invention to
provide an entirely new method of prescribing a non-pharmacological
prophylactic and therapeutic ORIP treatment regimen for preventing
DNA damage resulting from modern lifestyle, by means of a user
friendly portable device that administers, monitors, measures and
ensures compliance of the ORIP treatment regimen with the eventual
goal of minimizing the consequences of DNA damage.
[0029] It is also an object of the present invention to deliver the
maximal dose of ischemia in shortest possible time without patient
discomfort for inducing optimal system wide ischemic
preconditioning for increasing the threshold of organs to withstand
oxidative stress and DNA damage.
[0030] It is also an object of the present invention to place ORIP
dosing protocol under the direct control of the clinician who can
prescribe and monitor the DNA damage prevention regimen remotely in
real time. It is also another object of the invention to allow the
home-based self-administration of the ORIP treatment by a
chronically ill ambulatory patient at risk of oxidative stress and
DNA damage. It is yet another object to make the method and
apparatus user friendly and painless for the patient, the clinician
and any clinical personnel engaged in administering the ORIP
treatment.
[0031] It is yet another object of the invention to make ORIP
treatment easily deployable across the board in any
pre-intervention settings that involve damage to the DNA. It is yet
further object of the invention to treat, prevent or mitigate
oxidative stress and DNA damage resulting from exposure to
chemotoxic substances, high fat high calorie diets, smoking and
other lifestyle related causes. It is also an object of the
invention to provide an anti-aging device that decelerates the
process of aging by means of mitigating DNA damage, cell senescence
and accelerating repair of DNA damage.
[0032] Present invention meets these objectives by providing a
means for preventing, treating or mitigating the impact of DNA
damage to a healthy human tissue comprising of releasing ischemia
triggered cellular modulators (ITCMs) by means of non-invasively
inducing transient, repetitive and alternate cycles of ischemia and
reperfusion, each lasting not less than 1 minute and not more than
10 minutes, in one or more remote organs, in one or more sessions,
thereby increasing the tissue injury threshold for DNA breaks,
promoting apoptosis of damaged cell, preventing senescence of
damaged cell, and accelerating the process of DNA repair.
[0033] In one preferred embodiment, optimal remote ischemic
preconditioning system is implemented as disclosed in the parent
'259 application, that uses paired cuffs at two different
anatomical locations (both upper limbs or both lower limbs or one
upper and one lower limb etc.), which alternately inflate and
deflate rendering ischemic stimuli to a march larger volume of the
body in half the time and least patient discomfort.
[0034] Accordingly, the present invention is directed to devices,
systems, methods, programs, computer products, computer readable
media, software algorithms and other hardware components such as
pneumatic cuffs, air pumps, valves, transducers and modules for
controlling one or more operating parameters and components of the
ORIP apparatus by either an attending clinician or remotely by a
clinician not in attendance by sending and receiving programming
from a remote server or system, such as the Web interface.
[0035] These advantages in addition to other objects and advantages
of the invention will be set forth in the description which
follows, and may be learned by the practice of the invention. The
objects and advantages of the invention may be realized and
obtained by means of the software, algorithms, devices, remote
servers and combinations thereof particularly pointed out in the
appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1. An illustration of an ORIP treatment session in
progress.
[0037] FIG. 2. Block diagram of the elements ORIP apparatus and
each of the pneumatic cuffs.
[0038] FIG. 3. Sequence of equal & alternating
inflation/deflation cycles in left and right limbs.
[0039] FIG. 4. Sequence of escalating timing of inflation/deflation
cycles in left and right limbs.
[0040] FIG. 5. ORIP EMS/P3/CC web architecture in an acute
treatment scenario.
[0041] FIG. 6. Schematic representation of ORIP apparatus with RF
Module.
[0042] FIG. 7. ORIP web architecture in an acute/sub-acute
treatment scenario.
[0043] FIG. 8. Illustration of ischemic zones in different
embodiments of ORIP.
DETAILED DESCRIPTION OF THE INVENTION
[0044] Detailed description about the ORIP apparatus, its operation
and its variants claimed in the instant invention is found in
particular in the Ser. No. 12/898,259 application. Definitions of
terms are also set forth in the '259 application. Numerous
embodiments of treatment regimens were mentioned in the parent
application that remain relevant to enabling the method of the
present invention, and hence incorporated by reference herein.
Nevertheless, pertinent features of parent invention are reproduced
herein for placing the teachings of the present invention in proper
perspective.
[0045] The novel features of the non-pharmacological ORIP treatment
of the instant invention can be deployed in many different DNA
damage and oxidative stress scenarios for preventing, treating or
mitigating the impact of DNA damage to a healthy human tissue by
means of releasing ischemia triggered cellular modulators (ITCMs).
Such DNA damage may be caused as a result of an exposure to
ionizing radiation during a therapeutic or diagnostic medical
procedure. Such DNA damage may also result from exposure to
chemotoxic agents, or may be cause as a result of oxidative stress
resulting from lifestyle related causes or aging. In such DNA
injury situations, ORIP treatment acts by increasing the tissue
injury threshold for DNA breaks by down-regulating NF Kappa B,
accelerating the process of DNA repair through various cell repair
pathways, promoting apoptosis of irreparable cells, preventing
senescence of affected cells, so on and so forth.
[0046] In the following detailed description numerous specific
details are set forth in order to provide a thorough understanding
of the present invention for preventing, treating or mitigating the
impact of DNA damage to a healthy human tissue. Such method
comprises of releasing ischemia triggered cellular modulators
(ITCMs) by means of non-invasively inducing transient, repetitive
and alternate cycles of ischemia and reperfusion, each lasting not
less than 1 minute and not more than 10 minutes, in one or more
remote organs, in one or more sessions, thereby increasing the
tissue injury threshold for DNA breaks, promoting apoptosis of
damaged cell, preventing senescence of damaged cell, and
accelerating the process of DNA repair. However, so as not to
obscure the present invention, every minor detail may not be
covered. Nevertheless, it will be understood by those skilled in
the art that the present invention may be practiced without these
specific details. Accordingly, optimal remote ischemic
preconditioning (ORIP) is a technology platform that can be adapted
and implemented in a long list of clinical and lifestyle conditions
requiring protection from DNA damage and accelerated aging.
[0047] Based on the design features, networkability of the ORIP
apparatus and the physiological mechanism that triggers the cascade
of ischemia triggered cellular modulators (ITCMs), the clinical
utility of ORIP treatment can be classified as acute deployment,
sub-acute deployment or chronic deployment. Acute deployment of the
ORIP device treatment may be as brief as a single session, and may
be in an elective procedure pre-conditioning setting. While
sub-acute treatment regimen includes scenarios requiring a limited
time repeated ORIP dosing sessions ranging from a few weeks to a
few months. However, chronic treatment will be long term permanent
or semi-permanent use of the device.
[0048] These embodiments are herein described and illustrated
through self-explanatory drawings in FIGS. 1 through 8. In a
preferred embodiment the apparatus comprises of using a pair of
pneumatic cuffs wrapped around each of the limbs, for example left
upper limb 10a and right upper limb 10b. Alternatively the cuffs
can be used on the wrist. These pneumatic cuffs are very similar to
those used with self-inflating oscillometric sphygmomanometers.
These easy to apply cuffs, which can be used on any of the upper
and lower limb combinations, can either be used by a clinician or
the patient himself/herself without any assistance by simply
wrapping the cuffs around the patient's selected pair of limbs.
Separate air tubing connect both the pneumatic cuffs to an ORIP
Console 12 housing the mechanical as well electronic components
that operate both the cuffs automatically inflating and deflating
in accordance to a pre-defined algorithm protocol upon pressing the
Start or ON Button 14 on the ORIP Console. A series of protocols
may be permanently programmed in the ORIP Console providing as
options for the user to choose a particular ORIP regimen, or can be
delivered to the Console from a remote location as a prescription
from a remote clinician. For such remote wireless connectivity the
ORIP Console may incorporate a Communication Module which may be
wired or wireless 28 (WCM).
[0049] It should be noted at this point that in the various
wireless embodiments described herein, all client-server data
transfer between the wired or wireless nodes is implemented either
through the telecommunication network or the Internet, using
protocols such as but not limited to WAP (Wireless Application
Protocol) or HTTP or TCP/IP communication or SMPP (short message
peer-to-peer protocol) to and from the ORIP Console's wireless
communication module preferentially according to the availability
of the 802.11 and cellular data channels.
[0050] When the Internet connectivity hardware is either not
incorporated within the ORIP Device Console or when the Internet is
not accessible, a peer to peer communication can also be
established with another wireless communication device in the
vicinity via radiofrequency (RF) transmission between the RF
Modules embedded within the Console and the wireless communication
device (FIG. 6). Such wireless communication device can be a mobile
phone, a laptop computer or even a stationary communication
terminal placed within the radiofrequency range of the ORIP
Console. These wireless communication devices may in turn transfer
the data received from the ORIP Console to the ORIP network via the
Internet. If the ORIP device or such other wireless communication
devices in the vicinity support multiple communication modes,
communication is attempted first using a TCP/IP connection over
open 802.11 channels, second using GPRS-enabled bulk or stream
transfer, and finally SMS/MMS can be used as a fallback.
[0051] Each ORIP cycle comprises of simultaneous alternating phases
in each limb such as: [0052] a) an ischemic phase wherein first of
the two auto-inflatable pneumatic cuffs inflate to a cuff pressure
that significantly exceeds beyond the systolic blood pressure to
completely occlude blood flow to the patient's first remote organ
10a (left limb) for a pre-defined period that is not less than 1
minute and not more than 10 minutes, and, [0053] b) a reperfusion
phase wherein second of the auto-inflatable pneumatic cuffs
deflates to allow free flow of blood to second remote organ such as
the right limb 10b for a pre-defined period, which may not be less
than 1 minute and not more than 5 minutes.
[0054] A single ORIP session may comprise of not less than 2 and
not more than 5 of either escalating/deescalating/unequally/equally
timed phases of alternating cycles per limb, accomplishing twice
the ischemic body area for optimal release of the therapeutic ITCMs
in half the time required by a single cuff procedure thereby
resulting in more potent effect in a much shorter time without
significant pain or discomfort to the patient. Nevertheless, a
single cuff remote ischemic procedure may also be implemented to
combat DNA damage.
[0055] As illustrated schematically in FIG. 2 each cuff may have
its own corresponding air pump, which comprise of an air pump 16
with an inflate valve 18 to allow and sustain inflation during the
ischemic phase at a cuff pressure that is significantly above the
systolic blood pressure, and a deflate valve 20 to deflate the cuff
during the reperfusion phase such that when the first limb 10a is
in ischemic phase the second limb 10b is in reperfusion phase. Each
pump of the air-pumping module is connected to its corresponding
cuff through tube. A pressure transducer 22 for each cuff senses
pressure oscillations in the artery by changes in the
counter-pressure off the cuff thus measuring the cuff pressure
during an ORIP session. The pressure transducer may use either an
oscillometric, or a photoplethysmographic, or an ultrasonic, or a
thermal or an infrared transduction method to measure the minimal
blood flow occlusion pressure (systolic blood pressure) to set up
the maximal occlusion pressure (10-30% higher than systolic
pressure) in the ischemic phase for each of the cuffs.
[0056] In addition to these hardware components for each cuff,
there is a Microprocessor 24 that controls and operates both the
cuffs 10a and 10b, and a Display 26 that provides user interface to
start, monitor and review the ORIP data, display in a real time
graphic user interface the ORIP treatment protocol, the status,
interact with the clinician, receive treatment reminders, review
the prognosis of the treatment and provide the user means controls
and switch to start or stop device. The microprocessor is either
pre-programmed or programmable to automatically inflate and deflate
the pneumatic cuffs alternatively in predefined repetitive cycles
in predefined order of each of the two remote organs (limbs). The
console display and controls provide graphic user interface for
real time user interaction with the microprocessor and other
components that are stored in the microprocessor's memory bay which
may include but are not limited to the selection and initiation of
a particular ORIP session, calling for a readout of some previously
stored data or the like, or setting into the microprocessor patient
related data, as well as times and dates relating to specific ORIP
sessions and regimen.
[0057] In FIG. 1, the upper arms 10a and 10b of a human subject are
shown wearing automatic flexible inflatable and deflatable cuff for
occluding the brachial artery when inflated beyond the subject's
systolic blood pressure. Systolic pressure is the maximum arterial
pressure that is produced during contraction of the left ventricle
of the heart. A typical ORIP session begins when the user uses the
ORIP Console Start/On button 14 to first select the specific ORIP
regimen and then begins the process of inflating the pneumatic
cuff. The Console Microprocessor 24 either utilizes a predefined
target of inflation pressure or actually measures the systolic
blood pressure to estimate the target inflation pressure in each
cuff. Such target inflation pressure when predefined is not less
than 200 mm Hg, and when it is estimated, it is not less than 10%
and not more than 30% above systolic pressure in upper arm or
wrist; and not less than 210 mm Hg, or not less than 10% and not
more than 30% above systolic pressure in thigh. The Microprocessor
retrieves the user selected ORIP regimen from its memory and
initiates the ORIP session by inflating the first pneumatic cuff to
a pressure that is 10-30% greater than the highest expected
systolic reading using the oscillometric method. When the
oscillations cease the maximum systolic pressure is reached. An
ischemic zone is created distal to the inflated cuff. These
ischemic zones are illustrated in each of the FIGS. 1, 5, 6, 7 and
8 by shaded areas. The preferred remote organs for administering
the ORIP treatment regimen are but not limited to the extremities,
more preferably the upper arm of the upper limbs and thigh of the
lower limbs. For an ORIP session either both cuffs can be applied
to upper arms of upper limbs, or to wrists, or to thighs of lower
limbs or a combination of upper and lower limbs. As illustrated in
FIG. 8, a right upper arm cuff 10b can be paired with a right thigh
10c, or left upper arm cuff 10a can be paired with right thigh 10c,
or the cuffs can be applied to each of the right 10c and left
thighs 10d. As can be inferred from FIG. 8 larger ischemic zones
can be created with thigh cuffs as compared to upper arm cuffs as a
much larger tissue mass is exposed to the ischemic effect in legs
than in arms. As represented by the shaded areas FIG. 8 the
ischemic zones created in lower limbs are larger than those created
in upper limbs. Accordingly, the cycles of ischemic and reperfusion
phases in an ORIP session can be further varied depending upon the
remote organs selected for dosing.
[0058] The ORIP Console housing may also incorporate a Wireless
Communication Module 28 to receive and send feeds from and to the
clinician regarding the compliance to the clinician-prescribed ORIP
treatment regimen, or to alter the ORIP treatment regimen, or to
prescribe a new ORIP treatment regimen. The wireless communication
module may use WIFI, GPRS, TCP/IP or a telecommunication protocol
to transmit data to the Internet either directly (FIGS. 5 & 7)
or use peer to peer RF transmission through an RF-enabled handheld
communication device in the vicinity of the ORIP Console as
illustrated in FIG. 6.
[0059] A graphic representation of the pressure in each of the two
cuffs during ischemia and reperfusion cycles of a typical ORIP
session is presented in FIGS. 3 and 4. In a preferred embodiment in
FIG. 3 the ischemia and reperfusion phases are equal and
alternating, meaning that when one cuff is inflated the other one
is deflated. There is no overlap of the inflation and deflation
cycles in this embodiment. However, in another preferred embodiment
in FIG. 4 the ischemia/reperfusion cycles alternate at initiation
of the first cycle but the inflation time escalates with subsequent
inflation and there may be some overlapping of ischemic phase in
respective limbs as the ORIP session continues because the
deflation time remains constant in each limb. In gradually
increasing the duration of the ischemic phase, the pre-conditioning
effect may be more attuned to the natural physiological response to
the ischemic episodes.
[0060] FIG. 5 illustrates an embodiment in which the ORIP apparatus
is deployed in an acute or P3 (pre-procedure preconditioning)
setting such as in which ORIP regimen comprise of a single ORIP
session of not less than 2 and not more than 5 ischemia/reperfusion
cycles. Repeat sessions may be warranted depending on the condition
of the patient. FIG. 6 also illustrates the networkability of the
ORIP apparatus, although it will be understood by those skilled in
the relevant art that the ORIP treatment can be administered even
if the ORIP apparatus is not networkable. As described previously
the ORIP Console 14 may incorporate within its housing a wireless
communication module 28 to connect to a remote server 30, which
enables Internet connectivity using any of the Internet
connectivity protocols known to the prior art, such as WIFI, GPRS,
TCP/IP or a telecommunication protocol to transmit data to the
Internet either directly or using peer to peer RF transmission
through an RF-enabled communication device 32 in the vicinity of
the ORIP Console as illustrated in FIG. 6. Such RF-enabled
communication device may be a mobile phone, a laptop or any
computer connected to the Internet. The ORIP data, whether stored
or real time, can be accessed through Web interfaces designed for
the Administrator 34, the Clinician 36 and the patient 38 mostly in
sub-acute or chronic treatment settings, wherein, because of its
networkability, the apparatus can also be implemented with a single
cuff. In fact this method of mitigating DNA damage and delaying
senescence and aging of cells can be implemented with adequate
efficiency using a single automated cuff operated by a device that
is not networked.
[0061] Following are examples of how the preferred embodiments of
ORIP can be deployed in mitigating the effects of DNA damage. These
examples are only broadly illustrative of the scope of the novelty
of the invention disclosed, and do not limit the utility of the
ORIP procedure in any oxidative stress condition where the organs
and the vasculature is at risk of injury or compromised function on
account of sub-optimal regulation of cellular mediators of
protection against DNA damage, DNA repair, cell apoptosis, cell
senescence, cell mutation, cell mutagenicity, etc. The scope of the
novelty of the invention is also not limited to simultaneous
deployment of all the modules of the apparatus. For example absence
of communication module, paired cuff module, web interface module
or missing network architecture may still enable the invention
achieving its objective of mitigating DNA damage
[0062] P3 (Pre-Procedure Preconditioning):
[0063] Certain high DNA injury procedures in diagnostic and
therapeutic radiology and chemotherapy in medical practice are
performed on an elective basis. These procedures such high
radiation CT scans, such as coronary angiography, abdominal CT,
radiation and chemotherapy in practice of oncology, are schedule
ahead of time. ORIP treatment can be applied with the convenience
of short treatment administration time, maximal ischemic dosing,
patient comfort, and single touch command without clinician
supervision. The ORIP method of the instant invention accomplishes
the remote ischemic preconditioning in just 20-25 minutes
automatically with one push on the start button and without
continuously engaging a clinician in process that may take up to an
hour without the ORIP device. ORIP pre-procedure preconditioning
treatment can be completed in a single session comprising of not
less than 1 minute and not more than 10 minutes each of the
ischemia and reperfusion phases. At least 2 and not more than 5 of
equally timed phases of such ischemia and reperfusion cycles per
limb are administered in a single session. Alternatively the
session may comprise of at least 2 and not more than 5 increasingly
timed phases of ischemia cycles may be administered per limb. In
either way the entire ORIP treatment can be accomplished during the
time patient is prepared for the CT scan, radiotherapy,
chemotherapy session or any such exposure to ionizing radiation or
oxidative stress condition.
[0064] Chronic DNA Damage Prevention & Wellness Promotion:
[0065] ORIP can also be deployed in long term mitigation of DNA
damage, countering oxidative stress, or delaying aging as a
wellness device. As discussed earlier, modern lifestyle has
introduced many ways in which DNA damage can be intensified or DNA
repair can be impaired, resulting in surplus unrepaired DNA which
may cause point mutations, cell senescence, eventually causing
malignancies and accelerating aging. Clinicians can prescribe ORIP
therapy particularly in high-risk conditions. ORIP treatment can
not only afford protection against DNA damage, but can boost DNA
repair, reduce oxidative stress and thus mitigate the long term
risk of developing cancers and decelerate the process of aging.
[0066] ORIP treatment regimen in chronic treatment scenario
comprise of not less than 2 sessions per week and not more than 14
sessions per week, and each session comprising of not less than 2
and not more than 5 ischemic phases per limb, and not less than 2
and not more than 5 reperfusion phases per limb, each of the
ischemic and reperfusion phases comprising of not less than 1
minute and not more than 10 minutes of ischemia and reperfusion
respectively. As DNA damage and repair is an ongoing activity in
human body and aging and lifetime cancer risk is an inevitable
reality of life, ORIP treatment can continue lifelong if
necessary.
[0067] Radiotherapy & Chemotherapy Adjunct:
[0068] Apart from diagnostic radiation exposure, therapeutic use of
radiotherapy, chemotherapy and a combination thereof is also a
major cause of collateral DNA damage to the normal healthy cells.
Prognosis in radiotherapy and chemotherapy relies on the maximum
tolerable dose of cancer killing radiotherapy/chemotherapy
interventions. Because these interventions cause plenty of
collateral damage to the healthy cell population cancer treatment
is limited by the magnitude of deployable therapeutic doses. If
such collateral DNA damage to healthy cells is checked, the
practice of oncology will greatly improve in terms of cancer
treatment. Because ORIP treatment promotes DNA damage preventing
activities such as reducing inflammation, down-regulating NF Kappa
B, interrupting life cycle of damaged cells by inducing apoptosis,
down-regulating cell senescence, and at the same time promotes DNA
repair, it can have profound effect on the short and long term
prognosis of cancer patients who are treated with radiation and
chemotherapeutic agents. ORIP can thus enhance the overall efficacy
of cancer treatment and reduce the impact of the associated side
effects,
[0069] ORIP treatment regimen in such cancer patients undergoing
radiation or chemotherapy or a combination thereof, can be
prescribed by the clinician as adjunct to cancer therapy, and
comprise of two phases: [0070] a) An acute phase ORIP treatment
consisting of a single session minutes or hours prior to the
radiotherapy/chemotherapy session, such session comprising of not
less than 2 and not more than 5 ischemic phases per limb, and not
less than 2 and not more than 5 reperfusion phases per limb, each
of the ischemic and reperfusion phases comprising of not less than
1 minute and not more than 10 minutes of ischemia and reperfusion
respectively. [0071] b) A sub-acute phase ORIP treatment regimen
initiated not earlier than the third day subsequent to the
procedure whether radiation or chemotherapy or combination thereof,
and continuing until 6 months post-procedure, such regimen
comprising of not less than 2 sessions per week and not more than
14 sessions per week, and each session comprising of not less than
2 and not more than 5 ischemic phases per limb, and not less than 2
and not more than 5 reperfusion phases per limb, each of the
ischemic and reperfusion phases comprising of not less than 1
minute and not more than 10 minutes of ischemia and reperfusion
respectively.
[0072] The description of the present invention has been presented
for purposes of illustration and description, and is not intended
to be exhaustive or limited only to the novelty in the form
disclosed. Many modifications and variations as suited to any
specific use contemplated will be apparent to those of ordinary
skill in the art.
* * * * *