WO2011051357A1 - Therapeutic gas for the treatment of mitochondrial disorders - Google Patents

Therapeutic gas for the treatment of mitochondrial disorders Download PDF

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Publication number
WO2011051357A1
WO2011051357A1 PCT/EP2010/066288 EP2010066288W WO2011051357A1 WO 2011051357 A1 WO2011051357 A1 WO 2011051357A1 EP 2010066288 W EP2010066288 W EP 2010066288W WO 2011051357 A1 WO2011051357 A1 WO 2011051357A1
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use according
inhalation
oxygen
vol
therapeutic gas
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PCT/EP2010/066288
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French (fr)
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Bernd-Michael Löffler
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Priority to US13/504,821 priority Critical patent/US10117893B2/en
Application filed by Individual filed Critical Individual
Priority to EP10776328.6A priority patent/EP2493482B1/en
Priority to CA2775249A priority patent/CA2775249C/en
Priority to ES10776328.6T priority patent/ES2487630T3/en
Priority to CN201080048586.9A priority patent/CN102665735B/en
Priority to EA201200466A priority patent/EA022674B1/en
Priority to AU2010311448A priority patent/AU2010311448B2/en
Priority to JP2012535816A priority patent/JP5837501B2/en
Priority to HK12110412.5A priority patent/HK1175096B/en
Priority to UAA201203794A priority patent/UA102629C2/en
Publication of WO2011051357A1 publication Critical patent/WO2011051357A1/en
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Priority to US16/135,620 priority patent/US20190151354A1/en
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Definitions

  • Mitochondrial Disorders The invention relates to the use of gaseous oxygen for the production of a therapeutic gas for inhalation by pa ⁇ tients .
  • the Interval-Hypoxia-Training is a method of acclimatization to altitudes. In this process people inhale oxygen-deficient air (14 - 9% 0 2 ) through a mask what initiates acclimatization activities in the body. Cycli ⁇ cal changes between oxygen-deficient air and ambient air make this altitude training highly efficient.
  • the Chronic fatigue syndrome is a chronic disease which often causes invalidity. It is characterized by a paralyzing mental and corporal exhaustion/exhaustibility as well as by a specific combination of further symptoms. Beside chronic exhaustion, symptoms are, among others, headache, sore throat, joint and muscle pain, difficul- ties in concentration, disturbance of memory, less rest ⁇ ful sleep, sensibility of lymph nodes as well as lasting debasement of fitness condition after exertion.
  • Oxidative stress is a metabolic status in which an amount of reactive oxygen species (ROS) is build or available, that is beyond the physiological levels.
  • ROS reactive oxygen species
  • Those reactive oxygen species arise in line with metabolic processes of the mitochondrial electron transport chain and cyto- chrome-P5o-oxidases .
  • These oxygen species are the perox ⁇ ide anion radical 0 2 ⁇ , hydrogen peroxide (H 2 O 2 ) and hy- droxyl radical OH (Schmidt R. F., e.a.: Physiologie desteil, Springer, 2007, p. 957 ff.).
  • Ubiquinone also named UQ, co ⁇ enzyme Q, CoQ, Q or coenzyme Q10
  • Ubiquinone is a quinone derivative with a lipophilic isoprenoid side chain, structurally re ⁇ lated to vitamin K and vitamin E.
  • the reduced phenolic form is called ubihydrochinone or ubiquinol (Q3 ⁇ 4) .
  • Q10, coenzyme Q is an essential vector of electrons and pro ⁇ tons between complex I and complex II, respectively, and complex III of the respiratory chain.
  • the Q10 level is different in various organs and the highest levels are found in myocardial muscle cells. Q10 declines by raising age. Generally it is assumed that Q10 is no vitamin because the body is able to produce enough Q10 by self synthesis. But this is apparently in many situations not the case (e.g. chronic diseases), but also in "as healthy known probands" one can find extensive lowered levels of Q10, without an apparent external cause.
  • the standard value of Q10 is 0.8 - 1.15 mg/1, the preventive medical rated range is > 1.4 mg/1, the thera ⁇ Therapeutic area is > 2.5 mg/1.
  • the object of the invention is providing means to medi- cate mitochondrial disorders and to elevate the concen ⁇ tration of Q10 in plasma of patients.
  • the object is solved by use of gaseous oxygen for the production of a therapeutic gas for inhalation according to the main claim.
  • gaseous oxygen for the production of a therapeutic gas for inhalation by a patient who has been identified as a person with a mito ⁇ chondrial disorder or a Q10 deficiency, for the treatment of mitochondrial disorders or the Q10 deficiencies.
  • the use is preferred, in which the inhalation of the therapeutic gas is performed in at least two sections.
  • the concentration of the oxygen in the therapeutic gas has a different amount in the respective sections .
  • the concentration of the oxygen in the therapeutic gas is from about 15 Vol-% to about 9 Vol-%.
  • the concentration of the oxygen in the therapeutic gas is from about 30 Vol-% to about 55 Vol-%.
  • the use is especially preferred wherein the respective sections of inhalation last from 1 minute up to 60 minutes.
  • the use wherein the oxygen partial pressure in the patient is detected during inhalation is also preferred.
  • the mitochon ⁇ drial disorder or the Q10 deficiency to be treated is as- sociated with: cardiac insufficiency, arrhythmias, car ⁇ diac arrest, tinnitus, acute hearing loss, senile ablep- sia, age-related macular degeneration, parodontitis , gin ⁇ givitis, cancer, solid tumour, Attention Deficit/hyper- activity Disorder (ADHD) , autism, Attention Deficit Disorder (ADD), parkinsonism, dementia, Alzheimer's disease, olfactory disorders, migraine, neuropathic pain, pru- ritis, asthma, chronic obstructive pulmonary disease (COPD) , apnoea, dialysis, apheresis, incontinence, neu- rodermatitis , psoriasis, wound healing, type
  • An especially preferred use according to the present in- vention is to elevate or increase the plasma levels of coenzyme Q10 in a patient.
  • the main object of the invention is to provide a method for the treatment of a patient having mitochondrial disorders or coenzyme Q10 deficiencies, and that the method consists of administering a therapeutic gas to the patient, and that the therapeutic gas contains different levels of oxygen, forming either a hypoxic or a hyperoxic therapeutic gas that is administered to the pa- tient in a regime, in which the level is changed from one section to the other from hypoxic to hyperoxic and back to hypoxic and so on.
  • IHHT Intermittent Hypoxia-Hyperoxia-Therapy
  • hypoxia is described in the art as a danger ⁇ ous principle as the method is compared to obstructive- sleep-apnoea (OSA) .
  • OSA differs from IHHT, in that the intervals and the duration of Hypoxia sec ⁇ tions are regulated.
  • test persons were chosen and concluded the test.
  • the persons belonging to the control group respired ambient air through an air supply tube of the respiration appara- tus (tube not connected)
  • the treatment group respired for 6 minutes 12 Vol.-% O 2
  • 3 minutes 44 Vol.-% O 2 was repeated three times, so that altogether four cycles were completed, forming an inhala ⁇ tion session of 36 minutes.
  • the lowest value for pC0 2 was defined to 80%.
  • pTT paired T-Test, 2-tailed for unequally variance of the groups within the groups for indicated values be- fore/after treatment.
  • uTT unpaired T-Test between treatment group and control group .
  • a patient showing symptomatic disorders caused by chronic borreliosis was treated 1 minute with 13 Vol-% hypoxia and 9 minutes with 38 Vol-% hyperoxia in 6 cycles forming a session of one hour duration.

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Abstract

The use of gaseous oxygen for the production of a therapeutic gas for inhalation by a patient who has been identified as a person with a mitochondrial disorder or a coenzyme Q10 deficiency, for the treatment of mitochondrial disorders or Q10 deficiencies is disclosed. For the first time a non-invasive method is disclosed, upon what the body's own level of Q10 can be raised significantly without further interventions.

Description

Therapeutic Gas for the Treatment of
Mitochondrial Disorders The invention relates to the use of gaseous oxygen for the production of a therapeutic gas for inhalation by pa¬ tients .
It is known that inhalation of oxygen-deficient air is used for the acclimatization of human bodies to high altitudes, particularly with regard to journeys of people to high mountain areas like the Himalayas or Tibet. But also athletes make use of this method which is known as altitude training to advance their physical ability in standard conditions.
The Interval-Hypoxia-Training (IHT) is a method of acclimatization to altitudes. In this process people inhale oxygen-deficient air (14 - 9% 02) through a mask what initiates acclimatization activities in the body. Cycli¬ cal changes between oxygen-deficient air and ambient air make this altitude training highly efficient.
The Chronic fatigue syndrome (CFS) is a chronic disease which often causes invalidity. It is characterized by a paralyzing mental and corporal exhaustion/exhaustibility as well as by a specific combination of further symptoms. Beside chronic exhaustion, symptoms are, among others, headache, sore throat, joint and muscle pain, difficul- ties in concentration, disturbance of memory, less rest¬ ful sleep, sensibility of lymph nodes as well as lasting debasement of fitness condition after exertion.
It is supposed, that CFS might be a result of mitochon- drial disorders or oxidative stress, beside other unspe- cific diseases. Oxidative stress is a metabolic status in which an amount of reactive oxygen species (ROS) is build or available, that is beyond the physiological levels. Those reactive oxygen species arise in line with metabolic processes of the mitochondrial electron transport chain and cyto- chrome-P5o-oxidases . These oxygen species are the perox¬ ide anion radical 02 ~, hydrogen peroxide (H2O2) and hy- droxyl radical OH (Schmidt R. F., e.a.: Physiologie des Menschen, Springer, 2007, p. 957 ff.).
Normal organism cells keep their ability to absorb reduc¬ ing or oxidising substances alive by storing reserves of reducing or oxidising substances. An imbalance between these pools, which overcharges the normal function of re¬ pair and detoxication of cells and therefore causes a damage of all cellular and extracellular macromolecules , is called oxidative stress (David Heber, George L. Black¬ burn, Vay Liang W. Go, John Milner (Ed.) : Nutritional On- cology. Academic Press, 2006. p. 314).
A possible treatment of this disease consists in applica¬ tion of Q10 (ubiquinone) . Ubiquinone (also named UQ, co¬ enzyme Q, CoQ, Q or coenzyme Q10) is a quinone derivative with a lipophilic isoprenoid side chain, structurally re¬ lated to vitamin K and vitamin E. The reduced phenolic form is called ubihydrochinone or ubiquinol (Q¾) . Q10, coenzyme Q, is an essential vector of electrons and pro¬ tons between complex I and complex II, respectively, and complex III of the respiratory chain.
Some deficiency symptoms of Q10 also appearing may have different reasons. The current most known situation of reduction of Q10 by medication is administration of statines to decrease the cholesterol level and LDL. The synthesis of mevalonic acid gets blocked, which is a collective junction for the production of cholesterol or Q10. Consequences for the patients are partly extensive: muscle pain, restricted walking distance comparable to intermittent claudication, general faintness, tiredness. They are generally not worked therapeutically with.
There is a raising amount of different indications known for lowered Q10, and for giving significant amendments by substitution of Q10 to "therapeutic" Q10 serum level. These are, among others, cardiac insufficiency, migraine, tinnitus. Further there are correlations between lower Q10 levels and cancer, Q10 and immune system and depres- sions.
The Q10 level is different in various organs and the highest levels are found in myocardial muscle cells. Q10 declines by raising age. Generally it is assumed that Q10 is no vitamin because the body is able to produce enough Q10 by self synthesis. But this is apparently in many situations not the case (e.g. chronic diseases), but also in "as healthy known probands" one can find extensive lowered levels of Q10, without an apparent external cause. The standard value of Q10 is 0.8 - 1.15 mg/1, the preventive medical rated range is > 1.4 mg/1, the thera¬ peutic area is > 2.5 mg/1.
The object of the invention is providing means to medi- cate mitochondrial disorders and to elevate the concen¬ tration of Q10 in plasma of patients.
The object is solved by use of gaseous oxygen for the production of a therapeutic gas for inhalation according to the main claim. Thus the object is solved by use of gaseous oxygen for the production of a therapeutic gas for inhalation by a patient who has been identified as a person with a mito¬ chondrial disorder or a Q10 deficiency, for the treatment of mitochondrial disorders or the Q10 deficiencies.
According to the invention the use is preferred, in which the inhalation of the therapeutic gas is performed in at least two sections.
Especially preferred is the use according to the present invention wherein the concentration of the oxygen in the therapeutic gas has a different amount in the respective sections .
Especially preferred is the use according to the present invention wherein the concentration of the oxygen in the therapeutic gas is from about 15 Vol-% to about 9 Vol-%. Especially preferred is the use according to the present invention wherein the concentration of the oxygen in the therapeutic gas is from about 30 Vol-% to about 55 Vol-%.
According to the present invention the use is especially preferred wherein the respective sections of inhalation last from 1 minute up to 60 minutes.
Furthermore according to the invention the use is espe¬ cially preferred wherein the total time of inhalation lasts from 10 minutes up to 5 hours.
Also preferred is the use wherein the oxygen partial pressure in the patient is detected during inhalation. Exceptionally preferred is the use wherein the mitochon¬ drial disorder or the Q10 deficiency to be treated is as- sociated with: cardiac insufficiency, arrhythmias, car¬ diac arrest, tinnitus, acute hearing loss, senile ablep- sia, age-related macular degeneration, parodontitis , gin¬ givitis, cancer, solid tumour, Attention Deficit/hyper- activity Disorder (ADHD) , autism, Attention Deficit Disorder (ADD), parkinsonism, dementia, Alzheimer's disease, olfactory disorders, migraine, neuropathic pain, pru- ritis, asthma, chronic obstructive pulmonary disease (COPD) , apnoea, dialysis, apheresis, incontinence, neu- rodermatitis , psoriasis, wound healing, type 2 diabetes, overweight, obesity, metabolic syndrome, multiple sclero¬ sis, allergy.
An especially preferred use according to the present in- vention is to elevate or increase the plasma levels of coenzyme Q10 in a patient.
In other words, the main object of the invention is to provide a method for the treatment of a patient having mitochondrial disorders or coenzyme Q10 deficiencies, and that the method consists of administering a therapeutic gas to the patient, and that the therapeutic gas contains different levels of oxygen, forming either a hypoxic or a hyperoxic therapeutic gas that is administered to the pa- tient in a regime, in which the level is changed from one section to the other from hypoxic to hyperoxic and back to hypoxic and so on.
The "Intermittent Hypoxia-Hyperoxia-Therapy" (IHHT), as it is called by the inventor, is a new therapy method that can be used for a wide range of diseases that are correlated with mitochondrial disorders and/or coenzyme Q10 deficiencies. In the art there are methods known as intermittent hy¬ poxia ("Intermittent Hypoxia: From Molecular Mechanism To Clinical Applications"; Lei Xi and Tatiana V Sere- brovskaja (Eds.) 2009 Nova Science Publishers Inc. New York) . The main difference to known methods (Diving: Nor- moxia with Hypoxia and simultaneous Hypercapnia (eleva- tion of CO2 levels in blood) ; von Ardenne method: Nor- moxia Hyperoxia, method with ozone (Normoxia-Ozone) ; so- called Hypobaric Hypoxia: Hypoxia with simultaneous pres¬ sure reduction of the air to breath) is that a normobaric hypoxia (15 - 9% 02) hyperoxia (30 - 55% 02) method is used.
Furthermore, Hypoxia is described in the art as a danger¬ ous principle as the method is compared to obstructive- sleep-apnoea (OSA) . In contrast, OSA differs from IHHT, in that the intervals and the duration of Hypoxia sec¬ tions are regulated.
Surprisingly it was found, that the concentration of Q10 raises in the blood of the patients, if cycles of inhala- tion of hypoxygenic and hyperoxygenic gases follow each other. Thereby it is advantageous to carry out these cy¬ cles several times following successively one after the other and thereby forming a session and repeating the complete session in predefined intervals.
For the first time a non-invasive method is disclosed, whereby the body's own level of Q10 can be raised sig¬ nificantly without further interventions or medications. Up to now it was only possible to elevate the plasma lev- els by administering Q10 orally or parenterally to a pa¬ tient in need of such a medication.
By using cycles of inhalation of hypoxygenic and hyper¬ oxygenic gases it is possible to elevate the plasma lev- els of Q10 in a patient up to the therapeutic range of 2.5 mg/1 without any problem. As the plasma level of coenzyme QIO is believed to be highly related with many diseases of the heart, brain, eyes, lungs, bladder, kidneys, skin, nervous system, sense of hearing, and also with pain and cancer, it is a great advantage to elevate the plasma level in a patient without external administration of the coenzyme QIO. The body' s-own production of coenzyme QIO is stimulated by the inhalation of hypoxygenic and hyperoxygenic gases.
Further it was found that by a capable oral therapy with so-called "mitogen substances" (e.g. acetyl salicylic acid, vitamins, alpha liponic acid, minerals, Zn, Mn, etc.) the effect of the oral therapy with QIO can be clearly amplified. Consequently, the same applies to the method of the invention so that co-medication with mitogen substances may be carried out.
It is apparent from the description of the invention that the levels of oxygen in the respective hypoxygenic and hyperoxygenic gases may be adjusted and easily optimized for a certain disease. It is possible for a skilled arte¬ sian to optimize those levels using the teaching of the present invention without deviating from the scope of the claims given herein.
The following examples explain the invention in greater detail .
Example 1 :
18 test persons were chosen and concluded the test. The test persons get randomized after an initial check-up into a control group (N=8) and a treatment group (N=10) . Within three weeks all of the test persons graduated ten inhalation proceedings of 36 minutes in each case. The persons belonging to the control group respired ambient air through an air supply tube of the respiration appara- tus (tube not connected) , the treatment group respired for 6 minutes 12 Vol.-% O2 , afterwards for 3 minutes 44 Vol.-% O2. This cycle was repeated three times, so that altogether four cycles were completed, forming an inhala¬ tion session of 36 minutes. The lowest value for pC02 was defined to 80%.
After completion of the ten treatment units all test per¬ sons were examined again. The inhalation was arranged by using an ordinary respira¬ tion apparatus. Analogous apparatus are known from the IHT. Those apparatuses were accordingly modified, so that next to hypoxygenic gases also hyperoxygenic gases with an oxygen content of 30 - 55 Vol-% can be ventilated.
Monitoring of oxygen partial pressure of the test persons blood was performed using a commercially available equip¬ ment as for example given in DE 92 08 590 Ul . The results of the collected physiological parameters of the test persons are presented in Table 1. The values of NPE (3-nitro phenyl acetic acid) and citrulline have been measured in the urine, the values for MMS (methyl malonic acid) , Q10 (coenzyme Q10) , and Mito Act (mitochondrial activity) in the blood of the test persons. Table 1
ParaControl Treatment
meter group group
Mean SD pTT Mean : SD pTT uTT
NPE before 7,52 1 1 ,70 0,37 10,09 15,17 0,244
after 29,05 71 ,17 33,1 1 46,57
Citrulline before 5,89 3,39 0,94 8,29 9,59 0,845
after 5,38 6,05 7,59 4,46
MMS before 0,94 0,46 0,25 1 ,02 1 ,37 0,325
after 1 ,05 0,33 0,53 0,33
Q10 before 0,78 0,26 0,02 0,96 0,31 0,000 0,23 after 0,91 0,31 1 ,37 0,35 0,02
Mito Act before 86,28 12,41 0,16 84,74 6,59 0,004 0,77 after 94,03 5,14 94,57 4,31 0,84
Statistical analysis:
Mean: Mean value
SD: Standard deviation.
pTT: paired T-Test, 2-tailed for unequally variance of the groups within the groups for indicated values be- fore/after treatment.
uTT: unpaired T-Test between treatment group and control group .
Example 2 :
A patient showing symptomatic disorders caused by chronic borreliosis was treated 1 minute with 13 Vol-% hypoxia and 9 minutes with 38 Vol-% hyperoxia in 6 cycles forming a session of one hour duration.
A significant improvement of the skin structure and the aspect of the skin was achieved after 10 sessions. The improvement remained for about 3 months .

Claims

Claims
1. Use of gaseous oxygen for the production of a thera- peutic gas for inhalation by a patient who has been identified as a person with a mitochondrial disorder or a coenzyme Q10 deficiency, for the treatment of mitochondrial disorders or coenzyme Q10 deficiencies.
2. Use according to claim 1, wherein inhalation of the gas is performed in at least two sections.
3. Use according to claim 1 or 2, wherein the concentration of the oxygen in the therapeutic gas has a dif- ferent level in the respective sections.
4. Use according to any of the claims 1 to 3, wherein the concentration of the oxygen in the therapeutic gas is from about 15 Vol-% to about 9 Vol-%.
5. Use according to any of the claims 1 to 3, wherein the concentration of the oxygen in the therapeutic gas is from about 30 Vol-% to about 55 Vol-%.
6. Use according to any of the claims 1 to 5, wherein the respective sections of inhalation last from 1 minute up to 60 minutes.
7. Use according to any of the claims 1 to 6, wherein the total time of inhalation lasts from 10 minutes up to 5 hours .
Use according to any of the claims 1 to 7, wherein the oxygen partial pressure in the patient is meas- ured during inhalation.
9. Use according to any of the claims 1 to 8, wherein the mitochondrial disorder or the Q10 deficiency to be treated is associated with: cardiac insufficiency, arrhythmias, cardiac arrest, tinnitus, acute hearing loss, senile ablepsia, age-related macular degenera¬ tion, parodontitis , gingivitis, cancer, solid tumour, attention deficit/hyperactivity disorder (ADHD) , au¬ tism, attention deficit disorder (ADD) , parkinsonism, dementia, Alzheimer's disease, olfactory disorders, migraine, neuropathic pain, pruritis, asthma, chronic obstructive pulmonary disease (COPD) , apnoea, dialy¬ sis, apheresis, incontinence, neurodermatitis, pso¬ riasis, wound healing, type 2 diabetes, overweight, obesity, metabolic syndrome, multiple sclerosis, al¬ lergy .
10. Use according to any of the claims 1 to 9, for the increase of the level of coenzyme Q10 in the plasma of a patient.
PCT/EP2010/066288 2009-10-27 2010-10-27 Therapeutic gas for the treatment of mitochondrial disorders Ceased WO2011051357A1 (en)

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