Patent Application: US-201715610362-A

Abstract:
disclosed are means of inducing neuroregeneration and / or neuroprotection in patients with damage to the nervous system . in one embodiment , noble gas containing compositions are administered to a patient suffering from a neurological injury , said therapy is administered alone , or in combination with other therapies useful in the induction of neuronal protection / stimulation of neurogenesis . in one specific embodiment , patients are treated with noble gas compositions to restore neural function subsequent to radiation therapy or chemotherapy for neoplasia of the brain . in another embodiment , noble gas compositions are administered prior to , concurrent with or after radiation and chemotherapy in order to induce a protective effect on non - malignant cells without substantially interfering with efficacy of radiation and chemotherapy .

Description:
the invention provides means of selectively protect healthy tissue from radiation or chemotherapy by administration of noble gases and compositions containing noble gases . in one embodiment the invention provides for administration of noble gases and / or compositions containing noble gases that selectively protect non - malignant brain tissue from irradiation or chemotherapy . the invention provides compositions of matter , protocols and uses of noble gases aimed at reducing and / or ameliorating neurodegenerative effects of brain cancer targeted therapeutics . in one embodiment the invention teaches the use of noble gases with ability to provide anti - inflammatory and / or neuroprotective activities which mediate selective effects on non - malignant tissue , while allowing for chemotherapy and / or radiotherapy to target malignant tissue . in one specific embodiment , concentrations of noble gases are administered in a manner to selectively upregulate super oxide dismutase to non - neoplastic tissue , thus protecting endogenous non - malignant stem cells , for example in the dentate gyms and subventricular zone of the brain , while allowing for death , mitotic inactivation and autophagy of neoplastic cells found in the brain in response to radiation and / or chemotherapy . in another embodiment , noble gases are utilized post chemotherapy and / or radiation therapy to allow for amelioration of neurocognitive effects of said chemotherapy and / or radiation therapy . it is known in the art that tumor cells lose specific physiological functions that are found in non - malignant cells in order to focus energy expenditure and cellular activities on proliferation , apoptosis resistance , and metastasis . examples of such “ focusing of resources ” can be seen in the case of proteasomes , in which tumors lose several proteasomes found in non - malignant cells , thus reducing redundancy of protein degradation activity . given activity , proteasome inhibitors such as bortezomib , have been shown to selectively kill cancer cells , which have lost redundancy , whereas healthy cells do not succumb to proteasome inhibition due to existing redundancy of protein degradation pathways [ 1 ]. similarly , the current invention is based on the unexpected finding that tumor cells possess a reduced ability to evoke stem cell chemotactic responses after injury as compared to non - malignant brain tissue . in one embodiment the invention teaches the use of various stem cells for protection , treatment , and restoration of neurological function subsequent to chemotherapy and / or radiation therapy of brain tumors . in one embodiment , the use of noble gas compositions is tailored to reduce upregulation of apoptosis in cell types that are targeted by radiation therapy . specifically , it is known that radiation upregulates apoptosis in various cells of the central nervous system , including to regenerative neuronal populations . one such radiosensitive cell type that is described by the inventors as a target of intervention are the cells in the dentate gyms . it is known that localized exposure of young rat brain to x - rays produces neuronal hypoplasia specific to the granule cell layer of the hippocampal dentate gyrus , which is believed to be responsible for endogenous neuroregenerative neuronal activity . this brain damage causes locomotor hyperactivity , slowed acquisition of passive avoidance tasks and long bouts of spontaneous turning [ 2 ]. radiation induced neural deficit may be associated with altered distribution of afferent fibers in the molecular layer [ 3 ], reduction in ngf and bdnf [ 4 ], apoptosis of cells in the subgranular zone and the hilus of the dentate gyms [ 5 ]. in some embodiments of the invention , use of noble gas containing compositions are utilized as a means of upregulating expression of growth factors that are lost during events associated with administration of therapeutic radiation for the treatment of brain tumors . the effects of radiation on healthy brain cells are often associated with induction of apoptosis . for example , nagai et al systemically treated 90 four week old mice with 18 gy x - rays ( 0 . 45 gy / min ); 10 each were decapitated and the cerebrums were removed 1 , 3 , 6 , 9 , 12 , 18 , 24 , 48 , and 72 hours after irradiation . controls were 10 unirradiated mice . dna fragmentation analysis was carried out by agarose gel electrophoresis , and morphological analysis was by the tunel method . apoptosis of neuronal cells was detected by cerebral dna ladders , which were visible between 6 to 24 hr , peaking in 9 hr . according to the tunel analysis , radiation - induced apoptosis increased , with a peak at 9 hours , but decreased 24 hours after irradiation . apoptotic cells were always localized exclusively in the hippocampal dentate granule cells [ 6 ]. apoptosis in brain cells has been observed in other systems in response to irradiation , and has been attributed , in part , to p53 activation [ 7 ]. one of the potent examples of the importance of p53 in upregulating apoptosis is the proclivity of cells lacking p53 to possess an inherent degree of radioresistance , as compared to cells expressing p53 , which are relatively radiosensitive . specifically in malignant brain tumors : medulloblastoma and glioblastoma , there is a profoundly different radiation responsiveness . medulloblastoma is very sensitive to radiation therapy , whereas glioblastoma is highly resistant , and the long - term survival of medulloblastoma patients exceeds 50 %, while there are few long - term survivors among glioblastoma patients . p53 - mediated apoptosis is thought to be an important mechanism mediating the cytotoxic response of tumors to radiotherapy . in an experimental study , researchers compared the response to radiation of five cell lines that have wild - type p53 : three derived from glioblastoma and two derived from medulloblastoma . they found that the medulloblastoma - derived cell lines underwent extensive radiation - induced apoptotic cell death , while those from glioblastomas did not exhibit significant radiation - induced apoptosis . p53 - mediated induction of p21 ( bax ) is thought to be a key component of the pathway mediating apoptosis after the exposure of cells to cytotoxins , and the expression of mrna encoding p21 ( bax ) was correlated with these cell lines undergoing radiation - induced apoptosis . the failure of p53 to induce p21 ( bax ) expression in glioblastoma - derived cell lines is likely to be of biologic significance , since inhibition of p21 ( bax ) induction in medulloblastoma resulted in a loss of radiation - induced apoptosis , while forced expression of p21 ( bax ) in glioblastoma was sufficient to induce apoptosis . the failure of p53 to induce p21 ( bax ) in glioblastoma - derived cell lines suggests a distinct mechanism of radioresistance [ 8 ]. thus , in one embodiment of the invention , therapeutic noble gas compositions are administered in a manner to alter apoptotic molecules and their ratio in the body . specifically , the invention teaches that various concentrations of xenon gas , when delivered into circulation , either by inhalation [ 9 - 11 ], or administration of echogenic xenon liposomes [ 12 , 13 ], can be utilized to block p53 upregulation , and / or to block the ability of p53 to induce p21 ( bax ). the use of xenon has been reviewed by numerous authors in the art , which provide guidance as to details of administration [ 14 - 16 ]. importantly , the new and non - obvious aspect of the current invention is that application of neuroprotective properties of xenon to selective neuroprotection of non - malignant tissue , while allowing for radiation therapy to kill the tumor cells . it is to be noted that the invention envisions not only neuroprotection from radiation therapy , but from other therapies that are associated with efficacy in brain tumor treated , including in chemotherapy , targeted therapy , immunotherapy , and metabolic therapy . in one embodiment , noble gas compositions are utilized that suppress p53 upregulation in non - malignant cells , while allowing for upregulation in neoplastic cells . the importance of p53 and means of analyzing its expression may be gleaned from previous publications in the art . for example , a study compared adult p53 (+/+) to p53 (−/−) mice exposed to gamma - irradiation . apoptosis and neurogenesis were assessed up to 14 days following the injury . five - ten hours following gamma - irradiation , cells with tunel positive nuclei were identified within the subgranular zone of dentate gyms ( dg ) of both p53 (+/+) and p53 (−/−) mice . at the same time - points , pyknotic and shrinking nuclei were visualized by hoechst 33258 staining . furthermore , gamma - irradiation increased the number of proliferating cell nuclear antigen ( pcna ) positive cells with a peak at 5 - 10 h in both animal groups . pcna immunoreactivity was detected in cells exhibiting condensed nuclei as visualized by hoechst 33258 staining . neurogenesis , assessed by mitotic marker p34 ( cdc2 ) immunoreactivity , showed a biphasic response to gamma - irradiation both in p53 (+/+) and p53 (−/−) mice which was characterized by an early inhibition and a delayed stimulation . in p53 (−/−) mice , the time required by dg granule cells to recover from the lesion and to stimulate proliferation was significantly shortened in comparison with wild - type mice thus resulting in an accelerated neurogenesis . these data support the notion that following gamma - radiation p53 plays a role in regulating cell - cycle progression rate but it is dispensable for promoting apoptosis of dg granule cells [ 17 ]. examples of gases or gas mixtures employed as medicament for radiation protection : 1 .) 100 % by volume xenon ; 2 .) 70 % by volume xenon / 30 % by volume oxygen ; 3 .) 65 % by volume xenon / 30 % by volume oxygen / 5 % by volume nitrogen ; 4 .) 65 % by volume xenon / 35 % by volume oxygen ; 5 .) 60 % by volume xenon / 30 % by volume oxygen / 10 % by volume nitrogen ; 6 .) 60 % by volume xenon / 35 % by volume oxygen / 5 % by volume nitrogen ; 7 .) 60 % by volume xenon / 40 % by volume oxygen ; 8 .) 55 % by volume xenon / 25 % by volume oxygen / 20 % by volume nitrogen ; 9 .) 55 % by volume xenon / 30 % by volume oxygen / 15 % by volume nitrogen ; 10 .) 55 % by volume xenon / 35 % by volume oxygen / 10 % by volume nitrogen ; 11 .) 55 % by volume xenon / 40 % by volume oxygen / 5 % by volume nitrogen ; 12 .) 55 % by volume xenon / 45 % by volume oxygen ; 13 .) 50 % by volume xenon / 50 % by volume oxygen ; 14 .) 50 % by volume xenon / 45 % by volume oxygen / 5 % by volume nitrogen ; 15 .) 50 % by volume xenon / 40 % by volume oxygen / 10 % by volume nitrogen ; 16 .) 50 % by volume xenon / 30 % by volume oxygen / 20 % by volume nitrogen ; 17 .) 50 % by volume xenon / 25 % by volume oxygen / 25 % by volume nitrogen ; 18 .) 45 % by volume xenon / 55 % by volume oxygen ; 19 .) 45 % by volume xenon / 50 % by volume oxygen / 5 % by volume nitrogen ; 20 .) 45 % by volume xenon / 45 % by volume oxygen / 10 % by volume nitrogen ; 21 .) 45 % by volume xenon / 40 % by volume oxygen / 15 % by volume nitrogen ; 22 .) 45 % by volume xenon / 35 % by volume oxygen / 20 % by volume nitrogen ; 23 .) 45 % by volume xenon / 30 % by volume oxygen / 25 % by volume nitrogen ; 24 .) 45 % by volume xenon / 30 % by volume oxygen / 25 % by volume nitrogen ; 25 .) 40 % by volume xenon / 30 % by volume oxygen / 30 % by volume nitrogen ; 26 .) 40 % by volume xenon / 50 % by volume oxygen / 10 % by volume nitrogen ; 27 .) 35 % by volume xenon / 25 % by volume oxygen / 40 % by volume nitrogen ; 28 .) 35 % by volume xenon / 65 % by volume oxygen ; 29 .) 30 % by volume xenon / 70 % by volume oxygen ; 30 .) 30 % by volume xenon / 50 % by volume oxygen / 20 % by volume nitrogen ; 31 .) 30 % by volume xenon / 30 % by volume oxygen / 40 % by volume nitrogen ; 32 .) 20 % by volume xenon / 80 % by volume oxygen ; 33 .) 20 % by volume xenon / 30 % by volume oxygen / 50 % by volume nitrogen ; 34 .) 15 % by volume xenon / 30 % by volume oxygen / 55 % by volume nitrogen ; 35 .) 15 % by volume xenon / 50 % by volume oxygen / 35 % by volume nitrogen ; 36 .) 10 % by volume xenon / 90 % by volume oxygen ; 37 .) 10 % by volume xenon / 50 % by volume oxygen / 40 % by volume nitrogen ; 38 .) 10 % by volume xenon / 30 % by volume oxygen / 60 % by volume nitrogen ; 39 .) 10 % by volume xenon / 25 % by volume oxygen / 65 % by volume nitrogen ; 40 .) 5 % by volume xenon / 25 % by volume oxygen / 70 % by volume nitrogen ; 41 .) 5 % by volume xenon / 30 % by volume oxygen / 65 % by volume nitrogen ; 42 .) 5 % by volume xenon / 50 % by volume oxygen / 45 % by volume nitrogen ; 43 .) 5 % by volume xenon / 30 % by volume oxygen / 65 % by volume nitrogen ; 44 .) 5 % by volume xenon / 95 % by volume oxygen ; 45 .) 1 % by volume xenon / 99 % by volume oxygen ; 46 .) 1 % by volume xenon / 30 % by volume oxygen / 69 % by volume nitrogen ; 47 .) 1 % by volume xenon / 25 % by volume oxygen / 74 % by volume nitrogen . xenon or a xenon - containing gas mixture are further used to produce a medicament for the treatment of impairments of blood flow in the brain , to produce a medicament for the treatment of impairment of cerebral perfusion , to produce a medicament for the treatment of cognitive impairments , to produce a medicament for cerebral protection specific to non - malignant cells , to produce a medicament for the prophylaxis and / or therapy of impairments of cognitive performance , also postirradiation , to produce a medicament for the treatment of irradiation associated fibrosis , to produce a medicament for the prophylaxis of white matter damage , to produce a medicament for improving the oxygen supply in the brain , to produce a medicament for the treatment of post - radiation associated ischemia syndrome , to produce a medicament for promoting blood flow in the brain as well as reduction in associated pathologies . in addition , xenon or xenon - containing gas mixtures are advantageously employed as medicament for the treatment of states with oxygen deficiency associated with radiation damage , especially oxygen deficiency in the brain . for example , xenon or xenon - containing gas mixtures are employed in emergency situations such as the nuclear or dirty bombs . xenon or a xenon - containing gas mixture is also used to produce a medicament for improving the oxygenation of the brain . xenon or a xenon - containing gas mixture are further used to produce a medicament for the treatment of cognitive or cerebral dysfunction , in particular of postoperative cognitive dysfunction after neuronal irradiation . cerebral dysfunctions caused by irradiation relate to impairments of the microcirculation , of oxygen utilization and of metabolic functions . the medicament is thus also used to treat cerebral disorders such as impairments of the microcirculation , of oxygen utilization and of metabolic functions . gaseous xenon or xenon - containing gas mixtures are particularly advantageously employed for prophylaxis before exposure to radiation therapy . prophylactic administration of xenon or xenon - containing gas mixtures takes place for example preoperatively , intraoperatively or postoperatively . the provided medicament for cerebral protection of nonmalignant tissue and the indications mentioned , or the medicament produced directly on use , in particular in the direct vicinity of the patient , is for example a gas mixture which comprises from 1 to 80 % by volume ( based on standard conditions , i . e . 20 . degree . c ., 1 bar absolute ) xenon ( e . g . remainder oxygen ). the medicament which is administered to the patient comprises xenon in pharmacologically or therapeutically effective amount , in particular in subanesthetically or anesthetically effective amount . a medicament with xenon in subanesthetically effective amount is advantageous . subanesthetically effective ( subanesthetic ) amounts of xenon mean those amounts or concentrations of xenon which are insufficient for general anesthesia . these are in general amounts of up to 70 % by volume xenon , preferably up to 65 % by volume , particularly preferably up to 60 % by volume , in particular up to 50 % by volume xenon . pure xenon is accordingly metered into the patient &# 39 ; s respiratory gas in the stated concentrations . this means that the respiratory gas supplied to the patient comprises for example from 5 to 60 % by volume , 5 to 50 % by volume , 5 to 40 % by volume , 5 to 30 % by volume or 5 to 20 % by volume xenon . in special cases , e . g . for prophylaxis , especially during prolonged ventilation , a dosage of xenon in the respiratory gas with a low concentration , for example 1 to 35 % by volume , 5 to 25 % by volume or 5 to 20 % by volume xenon in the respiratory gas , may be advantageous . the medicaments , in particular gaseous medicaments , preferably comprise besides xenon one or more gases or substances which are gaseous at body temperature under atmospheric pressure . examples of gas mixtures which can be used are xenon - oxygen gas mixtures or gas mixtures of xenon and one or more inert gases such as nitrogen or a rare gas or xenon - oxygen inert gas mixtures . admixture of a gas to the xenon may be very advantageous if it is intended to introduce little xenon into the body . in one embodiment , noble gas containing mixtures are utilized to augment endogenous neural stem cells ( nscs ) activity so as to preserve neural function against side effects of radiotherapy . nsc are self - renewing , multipotent stem cells that generate neurons , astrocytes and oligodendrocytes . the medical potential of neural stem cells is well - documented . damaged central nervous system ( cns ) tissue has very limited regenerative capacity so that loss of neurological function is often chronic and progressive . neural stem cells ( nscs ) have shown promising results in stem cell - based therapy of neurological injury or disease . implanting neural stem cells ( nscs ) into the brains of post - stroke animals has been shown to be followed by significant recovery in motor and cognitive tests . it is not completely understood how nscs are able to restore function in damaged tissues but it is now becoming increasingly recognized that nscs have multimodal repairing properties , including site - appropriate cell differentiation , pro - angiogenic and neurotrophic activity and immunomodulation promoting tissue repair by the native immune system and other host cells . it is likely that many of these effects are dependent on transient signaling from implanted neural stem cells to the host milieu , for example nscs transiently express proinflammatory markers when implanted in ischemic muscle tissue damage which directs and amplifies the natural pro - angiogenic and regulatory immune response to promote healing and repair . in chronic stroke brain , nscs also have a substantial neurotrophic effect . for example , they promote the repopulation of the stoke - damaged striatal brain tissue with host brain derived doublecortin positive neuroblasts . a clinical trial is conducted in 20 patients with brain metastasis who receive 2 gy to 100 gy fractionated over 2 - 8 weeks . 10 patients are treated with 10 - 20 liters of 30 % xenon every other day during radiation exposure . an additional 10 patients are treated with similar radiation regimen and administered 10 - 20 liters of air every other day during radiation exposure . at 3 , 8 , 12 , and 24 weeks , preservation in cognitive function as measured by hvlt - r total recall score ( verbal learning and memory test ) is observed in the xenon treated patients . furthermore , verbal memory , as measured by the hopkins verbal learning test - revised ( hvlt - r ), cognitive flexibility as measured with the controlled oral word association ( cowa ), word fluency has measured with the controlled oral word association ( cowa ), working memory has measured with the wechsler adult intelligence scale — digit span , processing speed has measured with the wechsler adult intelligence scale — digit symbol , motor dexterity has measured with the grooved pegboard ( gp ), functional assessment , as measured by the functional assessment of cancer therapy - brain ( fact - br ), all improved in the xenon treated group . no acceleration of tumor growth is seen in patients receiving xenon as compared to air controls . 1 . obeng , e . a ., et al ., proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells . blood , 2006 . 107 ( 12 ): p . 4907 - 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type p 53 human glioma cells by adenovirus - mediated delivery of the p 53 gene . j neurosurg , 1998 . 89 ( 1 ): p . 125 - 32 . 8 . shu , h . k ., et al ., the intrinsic radioresistance of glioblastoma - derived cell lines is associated with a failure of p 53 to induce p 21 ( bax ) expression . proc natl acad sci u s a , 1998 . 95 ( 24 ): p . 14453 - 8 . 9 . laitio , r ., et al ., effect of inhaled xenon on cerebral white matter damage in comatose survivors of out - of - hospital cardiac arrest : a randomized clinical trial . jama , 2016 . 315 ( 11 ): p . 1120 - 8 . 10 . arola , o . j ., et al ., feasibility and cardiac safety of inhaled xenon in combination with therapeutic hypothermia following out - of - hospital cardiac arrest . crit care med , 2013 . 41 ( 9 ): p . 2116 - 24 . 11 . azzopardi , d ., et al ., moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia ( toby - xe ): a proof - of - concept , open - label , randomised controlled trial . lancet neurol , 2015 . 12 . britton , g . l ., et al ., in vivo therapeutic gas delivery for neuroprotection with echogenic liposomes . circulation , 2010 . 122 ( 16 ): p . 1578 - 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