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.

What I claim as my invention is: 
     
         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.