Patent Application
20240374553
The present invention relates to compositions and their use in methods for the prevention or treatment of pathologies, including neurodegenerative, cardiovascular diseases and different stages of coma.
Many neurodegenerative and cardiovascular pathologies are today still considered to be irreversible, such as Alzheimer's Disease (‘AD’), Parkinson's Disease, Creutzfeld-Jakob's Disease (CJD), different types and stages of coma, cardiovascular accidents (‘CVA’) including stroke, diabetes type III involving resistance to insulin in the brain, and neuro-immunodeficiency (leukocytes trafficking) in the brain-blood barrier (‘BBB’), which is the regulating seat of neuro-dynamics fluxes.
CVA diseases are broadly associated with a molecular pathology of cholesterol (‘CHO’), and the intermediate stages of which involve the accumulation and polymerisation of monomer-like atheromatous plaques. These plaques induce logical disorders in the kinetics of blood flow and cause the loss of integrity of the BBB, eventually conducive of a CVA, stroke associated with total or partial blockage of brain activity and memory capacity. The major protein component of these plaques is beta amyloid peptide Aβ.
The cholesterol molecule comprises four carbon rings denoted A, B, C and D (cyclopentano-perhydro-phenanthrene ring), five methyl CH3 radicals and eight asymmetric carbons (carbons 3, 8, 9, 10, 13, 14, 17 and 20, illustrated in
Esterification of sterols, including CHO LDL (cholesterol low density lipoprotein), is a collateral effect which is associated to the co-polymerization of cholesterol: the monomer of cholesterol (‘CHO’) can adopt a self-assembling configuration and a polymeric-like structure under UV radiation, derived from membrane cells proton H+ velocities. In the case of esterification, CHO is insoluble in haemoglobin (‘Hb’) and blood flow, and this property seems to favour fibrillogenesis, tangles and plaques mainly in blood, arteries, the brain and the blood-brain barrier (BBB).
We can consider CHO LDL as prominent co-factor of Reactive Oxygen Species (‘ROS’) and DNA alkylation mainly due to the presence of these five CH3 methyl radicals, conducive of DNA damage and possible losses of telomere integrity. This fact might provoke prominent disorders at cellular level and generate by-products including but not limited to prions, fragments, Tau proteins and promoters of β-amyloid (Aβ) plaques in neuronal tissue and whole brain areas, generally illustrated in
A number of correlations have been identified between infection with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), the causative agent of COVID-19 and viral involvement in AD. The angiotensin-converting enzyme 2 (ACE2) receptor is overexpress in AD brains and provides easy access into the brain for SARS-COV-2 and increases viral invasion. SARS-COV-2 inhibits the ACE2 receptor and contributes to neurodegeneration by decreasing production of brain-derived neurotrophic factor (BDNF). Additionally, SARS-COV-2's entry into cells was facilitated by the ApoE ε4 allele, increasing the risk of AD. Additionally, the existence of oxidative stress and neuroinflammation in AD patients has been found to increase the inflammatory response associated with COVID-19 and death from COVID-19. And AD is known to be one of the most common COVID-19 comorbidities and having AD increased mortality as well if infected with COVID-19 (Rudnicka-Drożak. E. et al. Int. J. Environ. Res. Public Health, 2023 February; 20 (3): 2146.
Bacterial agents and exogenous contaminants such as pesticides, nitrites, nitrates, dioxins-furans-PCBs-preservatives (endocrine disruptors), fluoro-aerosols (industries), insufficiently bio-degraded pharmaceutical molecules (hormones and parts of hormones-antibiotics from animal breeding), besides heavy and toxic metals (Aluminium Al3+ and other toxic metals (including Hg2, Mercury, especially in the form of Mono Methyl Mercury (‘MMM’)) all constitute molecular or elementary vectors (metals-atoms-elements) that are important and aggravating sources of oxidative stress of Reactive Oxygen Stress (‘ROS’), which inhibit the performance of synaptic cleft (neuro-mediators) and contribute to develop neurodegenerative pathologies, in some individuals quicker than in others according to their respective genetic potentials. An important point of ROS, oxidative stress is the formation of highly oxidative pathogens such as H2O2 or hydrogen peroxide and/or assimilated.
This phenomenon appears comparable to the increase of the entropy of the medium, which exists because of the relative duration of the integrity of the biological variable depending on the immune and genetic resistance and telomere depletion of individuals.
Pathologic cholesterol LDL can thus be considered as oxidative and mutagenetic and thus, as an agent of carcinogenesis and immunodeficiency. Therefore, pathologic cholesterol LDL is heavily responsible for neuropathic diseases among others pathologies, including but not limited to hepatic disorders.
Amongst neuropathic diseases, Alzheimer's Disease is a multifactorial pathology characterized by the formation of extracellular plaques integrated by the β-amyloid peptide (Aβ), the intracellular neurofibrillary tangles of the hyperphosphorylated tau protein and the presence of chronic neuroinflammation that causes progressive deterioration of memory and cognitive functions. Current therapeutic strategies to improve memory deficit aim at preventing the formation and accumulation of Aβ and the tau protein phosphorylation (Hampel et al., 2018; Hu et al., 2019, incorporated by reference herein). Beyond these targets, other common facts of the AD pathophysiology, such as oxidative damage and inflammation, may also be therapeutic objectives in order to slow down the memory loss progression (Salomone et al., 2012). The multifactorial origin of AD limits the design of effective drugs for AD prevention and/or treatment.
Thus, due to the complex interrelation between the different pathophysiological mechanisms involved in this disease, the use of therapies selectively addressed to reduce or block one possible cause of the disease does not seem to be adequate to reverse neuronal degeneration. On the contrary, pharmacological therapies addressed to act on all or most factors recognized today as responsible for the disease constitute a more effective a priori approach for the design of new generation drugs. These new strategies are known as “multi-target therapies” (Hopkins, et al., 2008). Thus, at present multi-target drugs for AD have been designed to promote inhibitory effects on the acetylcholinesterase (AChE) or ButyrylCholinesterase (BuChE) activities together with other relevant actions such as β-secretase inhibition, βA peptide anti-aggregation, improving the antioxidant status, acting as antihistaminic and/or cannabinoid receptor (CB1) antagonist, or metal chelator. In addition, other drugs have been designed to con-joint β-secretase inhibitory activity with metal chelating capacity effects or to obtain drugs modulating both γ-secretase activity and PPARγ receptors (Connolly et al. 2018; Hu et al. 2019; Ibrahim and Gabr, 2019; Tamagno et al., 2008). In recent years, emergent evidences support the implication of the innate immunity, particularly of microglia in the pathogenesis of AD (Heneka et al., 2015a). The protein aggregates deposited in AD brains are recognized by the microglia cell receptors and, consequently, triggering an innate immunity response, characterized by the release of several inflammatory mediators, who contribute to the progression of the disease (Heneka et al., 2015b). In addition, recent genetic studies have shown that several genes related to innate immunity are associated with the risk of AD development.
It has also been shown that in the space of the synaptic cleft, the migration of Ca2+ and Mg2+ and Zn2+ ions are inhibited or antagonized by bivalent toxic chelating ions such as Hg—Cd—Sn (bivalent), thallium, or trivalent Al3+, As3+ or hexavalent (Cr6+). Copper Cu2+ is a powerful competitor of Zn2+ in the synaptic cleft and can cause rupture of the Zn/Cu equilibrium in whole brain tissues, liver and pancreas tissues, and will affect the neuronal, liver or pancreatic activity, and will increase the Aβ formation in the context of Alzheimer's Disease, inducing anisotropy in the molecular BBB integrity.
The most common genetic risk factor for Alzheimer's Disease is the e4 allele of the gene for apolipoprotein E (APOEε4), which is present in approximately 50% of individuals with AD. APOEε4 heterozygosity triples the risk of AD compared with non-carriers; homozygotes have a sevenfold risk. Other less prevalent risk genes and familial tendencies have also been identified.
Mutations in the genes for amyloid precursor protein (APP, on chromosome 21), presenilin 1 (PS1, chromosome 14), and presenilin 2 (PS2, chromosome 1) cause autosomal dominant early-onset AD. These mutations account for the majority of familial midlife-onset AD, but represent less than 5% of all AD cases. Sortilin 1 (SorL1) mutations cause late-onset AD.
AD's core neuropathologic findings include extracellular amyloid plaques, intracellular NeuroFbrillary Tangles (NFTs), synaptic deterioration, and neuronal death granulovacuolar degeneration in the hippocampus and amyloid deposition in blood vessels. Cerebral Amyloid Angiopathy (CAA) may also be seen on tissue examination under nMRI, but are not required for the diagnosis. The “amyloid cascade” hypothesis posits that amyloid plaques interfere with synaptic activity and initiate a series of downstream effects that cause increasing inter- and intraneuronal dysfunction and, ultimately, cell death.
Although amyloid plaques may be sub-classified according to their composition, all contain forms of β-amyloid protein (Aβ). Aβ is an amino acid peptide formed by proteolytic cleavage of Amyloid Precursor Protein (APP) by β- and γ-secretase. The main products of this cleavage are Aβ1-40 and Aβ1-42. A relative surplus of Aβ1-42 predisposes toward amyloid aggregation into oligomers and fibrils, which assemble into amyloid plaques.
An important role for amyloid in Alzheimer's Disease pathophysiology is implied by the fact that the proteins encoded by APP, PS1, PS2, SorL1, and APOEε4 are all associated with amyloid generation, processing, and/or trafficking. However, several lines of evidence indicate that amyloid plaques are not the primary cause of AD. Amyloid plaque burden (a) can be found in cognitively normal adults, (b) does not correlate with degree of cognitive impairment in individuals with AD dementia and, (c) is associated with cognitive improvement in some AD mouse models.
Tau (Tau), a brain-specific protein involved in microtubule assembly, is essential for normal axonal growth and neuronal development. However, hyperphosphorylated tau protein forms intracellular aggregates which form into helical filamentous NFTs that are deposited preferentially within neurons of the mesial temporal lobe (especially hippocampus), lateral parietotemporal region, and the frontal association cortices. The NFTs are recognized as a primary biomarker of AD and are also present in numerous other diseases termed tauopathies. The critical role of NFT in AD pathophysiology is suggested by the correlation between location and density of Tau NFT and the symptoms and severity of AD dementia. Moreover, some studies have demonstrated that Aβ oligomers are not toxic unless Tau proteins are also present.
The distribution of neuronal cell death and synapse loss is similar to that of NFT. In typical AD, the death of neurons in the nucleus basalis of Meynert leads to a deficit in acetylcholine (Ach), a neurotransmitter involved in memory. This cholinergic deficit is the target of most current treatments. In the brainstem, loss of median raphe and locus coeruleus neurons leads to deficits in serotonin and norepinephrine, respectively. Abnormal cerebral serotonergic and adrenergic activity likely contribute to dysphoria and insomnia in AD
In addition, certain toxicological considerations indicate that the pathology of Alzheimer could propagate to other neuronal tissues in a transmissible prion mode increased by the ROS oxidative stress, by endogenic contaminants (with cholesterol LDL as “monomer” promoter prion of Aß plaques) and exogenic molecules.
Aβ-APOEε4 plaques are thus mainly, at different molecular stages, resulting from cholesterol molecular pathology initiated in membranes, wherein the status of protons as donors or acceptors is strongly perturbed by the process of CHO esterification, compromising the membrane cleft integrity.
Several references, lastly in March 2019, (www.sciencemag.org/news/2019/03/another-major-drug-candidate-targeting-brain-plaques-alzheimer-s-disease-has-failed), indicate that laboratories leading in research into pharmaceutical pathways aimed at reducing or destroying amyloid plaques and Tau proteins have abandoned their efforts through failure. Thus, ddespite considerable efforts by laboratories, known medications still only halt the symptomatology of Alzheimer's disease temporarily, but have side effects from low to severe depending on the stage of the patient's AD.
The present approach aims to introduce novel pharmacological engineering, as compositions, protocols and experimental physics processes, for mitigating and treating such pathologies. https://www.sciencemag.org/news/2019/03/another-major-drug-candidate-targeting-brain-plaques-alzheimer-s-disease-has-failed
According to an aspect of the invention, there is provided a composition comprising Zinc CARBONYL (ZNCO) and silicon SiHR57™ in the form ((CH3)3Si2(OH)3—R(COOX)) for use as a medicament or in therapy. More particularly, according to an aspect of the invention, there is provided a composition comprising Zinc CARBONYL-ZNCO in the form of an organic compound soluble in water and having a carbonyl function complexed with zinc, and silicon SiHR57 in the form of ((CH3)3Si2(OH)3—R(COOX)), wherein X is selected from the group comprising sodium, potassium and lithium, and R represents O, O2, OH—C3H4, Sodium silicate, Potassium silicate or Lithium silicate is OH—C3H4, for use as a medicament or in therapy.
“Zn-FLNT4” described herein will be understood as an organic compound soluble in water and having a carbonyl function complexed with zinc. The structure and process for the preparation of organometallic complexes including zincZn-FLNT4 (Zinc CARBONYL (ZNCO) is described in detail in France Publication No. FR2708002 and PCT Application Publication No. WO/1996/023089, each of which are hereby incorporated by reference in their entirety.
It will be understood that the silicon atom in ((CH3)3Si2(OH)3—R(COOX)) is hypervalent (pentavalent). This principle is well established in the field of chemistry. For example, https://pubs.acs.org/doi/10.1021/ja0162616; http://www.f.u-tokyo.ac.jp/˜kanai/seminar/pdf/Lit_T_Ito_B4.pdf; and https://www.scripps.edu/baran/images/grpmtgpdf/Hafensteiner_Nov_03.pdf, each of which are hereby incorporated by reference in their entirety.
In a variant of these embodiments, the Zinc CARBONYL (ZNCO) component is preferably associated with a D-fructose molecule.
In embodiments, the organic compound soluble in water and having a carbonyl function may be at least one selected from a sugar, an oligosaccharide, a disaccharide, an enzyme, a coenzyme, a protein, a peptide, an amino acid, a hormone, a steroid, a prostaglandin, a neurotransmitter, a vitamin, an ester, a carboxylic acid, a ketone, an anhydride, and an antibiotic.
The composition may be for use as a medicament or in therapy, in combination with a whole lung lavage procedure.
Alternatively, in at least some embodiments, the composition may be for use in a method for mitigating neurodegeneration associated with exposure to at least one matter selected from solar energetic particles, galactic cosmic rays and extra-terrestrial radiation. These embodiments of the composition may usefully be incorporated into one or more human food supplement(s) for delivery.
According to another aspect of the invention, there is also provided a method of aligning the spin of molecules. In embodiments of the composition presented herein above and described hereinafter, comprising the steps of locating at least one conduit adjacent a source of electromagnetic radio waves (EM-RF), causing the composition to flow through the conduit, and generating an EM-RF within the source, for subjecting composition in the conduit to the generated EM-RF. The conduit may include, but is not limited to, the inlet and outlet of a controlled-rate syringe.
In an embodiment of the method suitable for pathology mitigation, for minor or early pathologies, and for longer-term treatment associated with high patient susceptibility to EM-RF, the EM-RF may be generated with intensity in the range 0.05 Tesla to 0.3 Tesla. Alternatively, in an embodiment of the method suitable for advanced stages of pathologies, the EM-RF may be generated with intensity in the range 1.5 Tesla to 3 Tesla.
Embodiments of the method consider the generation of the EM-RF under a variety of forms, each dependent upon one or more of patient morphology and cellular aspects, pathology and stage thereof, availability of equipment and more, with such forms including a (B) permanent EM-RF, a pulse-modulated EM-RF or an oscillating EM-RF.
An embodiment of the method may comprise the further steps of i) administering the EM-RF-subjected composition to the patient, ii) locating at least an area of the patient including the administered composition, iii) positioning, typically the patient's cranium or a portion thereof, adjacent a magnetic resonance imaging (MRI) apparatus, and iv) generating a second EM-RF with the MRI apparatus. This can then subject the area including the administered composition to the generated second EM-RF. In a variant of this embodiment, the second EM-RF may be generated with intensity in the range 1.5 Tesla to 3 Tesla.
Embodiments of the method consider the administration of compositions as described herein. The administration can be selected from oral ingestion, endonasal or intranasal spray, dermal probe, transdermal patch and intraperitoneal or intracranial injection.
According to a further aspect of the invention, there is also provided a cyclodextrin particle for delivering the composition presented hereinabove and described hereinafter.
Embodiments of the cyclodextrin particle may be shaped as a three-dimensional cage with at least one aperture, and may optionally be shaped as a torus. This is depicted in
Embodiments of the cyclodextrin particle may further comprise silicon-germanium nanoparticles or picoparticles located on an inner surface of the cyclodextrin particle.
Embodiments of the cyclodextrin particle may further comprise Zinc carbonyl located on an outer surface of the cyclodextrin particle.
Other aspects of the present invention are as stated in the appended claims.
Embodiments of the present invention will now be described by way of example only, with reference to accompanying drawings, which are:
The inventor has been working for many years on the biophysical aspects of biological material and therefore DNA-RNA (intronic quantum biology). The intronic quantum concept of experimental theory of bio-physics mechanisms associated with DNA-RNA sequences in living genetic material is considered a prominent problem.
It has been shown that human DNA encodes only 5% of the classical biological reactions known as exonic 95% (Intronic 5%) of the germplasm appears to be missing visible participation in the biological material protein. This non-coding part of our DNA (95%) has been defined as intronic RNA. An intron is a non-coding DNA sequence interrupting the coding sequence of a poly partite gene (opposed to exon). An intron can be seen as a fragment of a gene located between two exons. Introns are present in immature mRNA and absent in mature mRNA. For the past 10 years, biologists have been confident that intronic non-coding parts play an important role in genetic and protein synthesis reactions, contrary to accepted initial ideas that the intron part of DNA serves no purpose.
These immature RNA introns could induce real genetic reactions, intervene in immune defense reactions, and disappear once their mission is complete. One might consider immature RNA introns that can be assimilated to particular biological messengers. Immature RNA introns could transmit their information according to mechanisms as well as biophysical (quantum signals), non-classical chemical and therefore molecular principles. Immature DNA-RNA sequences may be considered to encode real, but stealth, proteins which dematerialize in the biological medium, upon receipt of the signals transmitted by the immature RNA sequence by the genetic material.
On this basis, several researchers have envisaged a non-molecular, but bio-physical system, in which the immature RNA genetic material transmits quantum-type signals at specific frequencies, mainly in the ultraviolet (UV) spectrum. One of the strong ideas of the experimental theory provides for the presence of an N—H (plasma of hydrogen) within the DNA double helix, which has been developed in a third catenary or strand of DNA. This plasma alone could explain the emitted or associated UV radiation of the mRNA material, which would bio-quantitatively encode stealth proteins. Describing these stealth proteins may be 10−3 s to 10−5 s does not prove that they do not exist, but have the kinetic time to transmit quantified information flows. The logical consequence of the amplification of these quanta of energy lies in the collateral reasoning for the maintenance of the emitted signal, in order to avoid entropy of the biological material.
There are very few elements in our biological material that could sustain such signals. The inventor has natural elements such as Silicon and Germanium, or Sulfur S32, therefore tetravalent elements, wherein both Silicon and Germanium possess opto-quantum properties, i.e. they accept radiation from a source or emit it under precise experimental conditions.
The effects of silicon on different organs and functions are scarcely known, although there is growing evidence of its role in mineralization, cardiovascular system, skin, immunity, as well as brain (Jurkic et al., 2013). It has been suggested that silicon consumption in western countries is reduced (Robberecht et al., 2009). Thus, the addition of this mineral to certain food, in addition to improve nutrition will contribute to improve different health key functions.
Studies carried out with organic Silicon G57 by our research have demonstrated the great antioxidant and neuroprotective capacity of this metal (Garcimartin et al., 2014; 2015a). In addition, the consumption of organic Silicon G57 improved the brain antioxidant status of rats intoxicated with aluminium, decreased learning capacities of these animals (Gonzalez-Muñoz et al., 2017). We have also observed the effect of this product on hyperlipidaemia, as well as a reduction in the fatty liver progression in animal model when silicon is added to meat matrices as a functional ingredient (Garcimartin et al., 2015b; 2017).
The present approach thus considers compositions based upon Zinc CARBONYL-ZNCO and Silicon 45-0046 (derived from Silicon G57™), in simultaneous activities on several processes involved in the development of the AD and stages, as a multi-target adapted to inhibit the AChE enzymes, β-secretase and γ-secretase activities; and to reduce the fibrillogenesis of the BA peptide, in order to attenuate the intracellular generation of free radicals and the release of nitric oxide (NO) by the microglia.
The present approach considers the following compositions:
A first ‘Phase II’ protocol relies upon the use of magnetic resonance imaging (MRI) apparatus to induce spin alignments, as a preliminary method to facilitate the transportation and dissolution of prion species out of the BBB and brain tissues, by means of solvents and captors of problematic molecules ROS reversing the effect of toxic agents. Use of external rotating and oscillating magnetic fields B (extracranial) permanent (lanthanides alloys) or pulsed (solenoids). The present approach further considers the use of a vertical or longitudinal cylinder (entire body introduction), for instance composed of several magnetic layers (possibly 7 to 10) generating permanent or pulsed vector fields, with each part of a cylinder isolated from others with bismuth foil or plaques.
The present approach may be taken as a reverse cholesterol LDL methodology for mitigating the toxic formation of Aβ plaques-tangles-APOEε4 and prevention of Cardio Vascular Diseases CVD and Cerebral Vascular Accidents CVA (strokes) but also the transmission of prion molecules in total neural brain tissues-CNS, Aβ plaques (as responsible of future molecular diseases, and/or inflammation and/or immunodeficiency).
As with COVID-19 infection, an infected, intubated patient in the Intensive Care Unit (ICU) are likely experiencing ROS induced by toxic molecules or vial genes. The inventor has postulated that in Alzheimer's disease patients, they too experience ROS and pulmonary complications such as pulmonary stroke and thus, can also benefit from the protocols used to address COVID-19 pulmonary complications. The methods disclosed pertain to patients under intubation (decision) and with severe pulmonary stress. The treatment of COVID-19 infection or AD addresses, as an initial method of treatment, cleaning alveolar structures (with help of WLL) or neuronal tissues (possibly via intranasal administration when also utilizing medicaments or therapeutic agents to by-pass the BBB (which itself has problems with molecular weight due to steric effects of the medicaments or therapeutic agents (steric congestion due to hemosiderin proximity)). Therefore, cleaning from the alveolar structures mechanically and with incorporation of protectant(s) of alveolar structures and chelating agents to destroy/dissolve toxic by-products as well as well as hemosiderin and CHO false polymers. The goal is to protect the alveolar functions and prevent aggregation of by-products of ROS as well as CHO copolymer(s)/plaques and hemosiderin formation. This observation is supported by conclusions of recent Chinese studies and elsewhere implicating neurological impacts (e.g., memory loss, ageusia and anosmia) and localized neural tissues affected as a result of COVID-19 infection(s). The detection of hemosiderin in AD brain has also been seen at Argonne Laboratories, US, these effects are also noted to be the by-products, hemosiderin and CHO (Cholesterol plaques), APO (accelerating Aβ-amyloid production), and the result of ROS mechanisms which block the synaptic transmission(s). Identical contaminants and toxic effects have been observed in the synaptic clefts in AD patients.
The mechanisms of ROS (Reactive Oxidative Stress) can be mitigated if patients can follow the protocols with 2 to 3 intensive sessions per month or more, and prevented through periodical sessions justified by genetic factors. Under the Phase I protocol, a patient may wear a monitored and programmed multi-geometric device around their head, potentially daily and for up to several hours, in order to target the CNS neural brain areas to be treated. Real-time MRI imagery under the Phase II protocol rapidly establishes the best vectors and routes of the SiHR57 composition, in order to decrease the stages of Alzheimer Disease.
The methodology uses the dissolution properties of several compounds mainly ZnFLNT4 (cyclic molecule) (Zinc CARBONYL (ZNCO) associated to Zinc, as main solvent of Aβ plaques and prion fragments, Tau proteins (self-assembly or polymerized structures and degraded form), APOEε[4], hemosiderin degraded, CHO polymerized form, self-assembly.
Silicon complex compound as (protector), cyclodextrins (αβγ) as secondary (solvents), cyclodextrins as monomer and/or polymerized form and/or ursodeoxycholic acid as solvent (
Reconstruction of neuronal tissue with the use of pluripotent stem cells applied (outside BBB) to the neuronal tissue and mainly to glial cells and astrocytes, can be stimulated under magnetic NMR and electro-Magnetic frequencies (radio waves) and induced by MHD-MGD (
A rebuilding protocol can be considered with master stem cells, but considered to be executed only after the dissolution process of Aβ plaques and prion fragments, Tau proteins (self-assembly or polymerized structures and degraded form)
Cyclodextrins and Haemoglobin (Hb); Hemosiderin (in contaminated tissues) are active under, and can be eliminated from BBB though, magneto hydro dynamics (‘MHD’)-magneto-gas-dynamics (‘MGD’) processes: protons transportation H+ concept and process as molecules in three dimensional cages (
The BBB is considered as “a physical tube or geometrically developed sphere (if we consider all the brain as final structure), interface membrane or an envelope.” And in the process of neurulation, one can verify that, the primitive laminar (neural tube) will be transformed under genetic tensors, in ectoderm, endoderm and mesoderm, with final shape of a tube.
BBB-CNS is assimilated to a MHD system where heme ions Fe2+ (atomic ions current ni) are circulating and developing magnetic fields (vectors). When the ROS is increasing the Fe3+ will create sub-aggregates through the BBB and the migration of heme Fe3+ under ROS in the neuronal cleft will be considered as the collateral source of biodegraded molecules (in addition to Aβ plaques and prion fragments) blocking the cleft communication and neurotransmitters mediators.
Haemoglobin presence in the cortex under active ROS will be degraded and will generate collateral products in neuronal tissues, prions, tangles and contaminants (fibrinogens), whereby the BBB will be considerably disturbed, the synaptic activity will be perturbed or destroyed. The degradation of Haemoglobin in brain tissues results in the deposition of hemosiderin, an insoluble form of Fe+2 which is a major form of iron-storage protein and closely related to neurological disorders—and strokes—as the pumps within the membrane are blocked, the mechanical disorders has been verified by micro pumps at lab (time species transport femtosecond) by several authors. The elaboration of a preventive or curative drug (or even a functional food) must, by its components, be able to block ROS contaminants such as Aluminium Al3+ and other toxic metals (including Mercury, Hg2+ and especially in the form of (Mono Methyl Mercury) and other contaminants as well as Dioxins.
The SiHR57 compositions can fight against oxidative stress but also potentially dissolve the Aβ protein plaques, but also block the adverse effects of free cholesterol as promoter or in its aggregated form self-assembly which will become a cofactor in the presence of Aβ protein.
The presence of Haemoglobin (heme nuclei) as illustrated in
Regarding hemosiderin the degraded protein with iron content can be verified with XRF (radiation tools) Argonne Laboratory DOE USA. Hemosiderin is an iron paramagnetic molecule which could be used in MHD—magnetic vectors and be eliminated when solved/dissolves through the BBB.
Our approach is to create SiHR57 products (several formulations and protocols) that will aim at preserving a reducing state in membranes or assimilated to membranes by means of molecules and atoms that act as reducing agents and particularly Zinc-Zn2+, Zn-FLNT4 (Zinc CARBONYL (ZNCO) and Silicon Si+4. Our approach consists in activating the mechanisms of dissolution of the long protein chains Aß and fibrinogens and thus reducing them to structures less sensitive to the states of peroxidation, the presence of agents Zn2+, Si4+ reducers can chemically allow it, so the medium will be protonated H3O+ non peroxidised, [—O—O-] thus reducing oxidative stress of ROS.
In the pre-treatment of prions and plaques and fibrinogen products one will first apply permanent magnetic B (Ln3+ alloys and solenoids (pulsed) and EM (pulsed) vectors on preventive or curative or fibrinogen monomers in a quasi-polymerized form.
It should be noted that the 1.5 T-3 T fields will cause spin alignments of biomolecular species in fibrinogen form, such as Aß plaques or aggregated cholesterol complexes.
This phenomenon is possible at the atomic level by aligning the spins. In the phenomena of polymerizations of the plaques and/or prions there exists a spin-orbit coupling which preserves the anisotropy of unstable and/or peroxidized molecular forms.
Spin orbit coupling is a quantum-magnetic dipole-type discussion in a magnetic field. Interesting experience with Ln+3 (lanthanides) including Gd3+ and labelled Tc3+. Exposures to 1.5 T-3 T and well-calibrated exposure time limits, in order to avoid possible overheating of water and tissues. A consideration would be to limit the background noise of the molecule of water as much as possible compared to the signal.
The protocols can be integrated into an exogenous or endogenous therapeutic approach (nanoprobes) to be coupled with simple or complex chemical and molecular agents orally, intravenously, intracranial or intranasal or by endothelial nasal application via pulsed aerosols. Pre-treatment in the laboratory of compositions by permanent magnetic field B-Lanthanides alloys, Permanent or solenoids/Pulse-0.05 T-0.1 T-1.5T-3 T Magnetic vectors and/or EM and/or 1.5 T-3 T. The pre-treatment excites the solutions to be administered and allows for testing the stability of molecular conformations. The homogeneous state of the solutions elaborated can be achieved by using ultrasonic apparatus.
Analyses (elucidation of NMR structures-GC-MS-LS) make it possible to gauge the couplings of active products in order to obtain a better response in the cerebral environment. In order to optimize the active molecules SiHR57, the goal is to use in the very short term (a few weeks) non-invasive technologies that safely allow to follow the real-time course of drugs administered in animals and/or the human (human neuro imaging) and therefore to better target and know with extreme precision the active areas and the response of the neuronal environment in the presence of drugs developed by the laboratory. It is possible to accurately determine the ability of products to cross BBB and gauge the pharmacokinetics of products and determine with great accuracy the allowable quantity of drugs and thus the bioavailability of drugs destinated to brain affected areas. It is also possible to determine the intrinsic activity of drugs and control the results obtained by imaging. Neuro-imaging and cardiovascular imaging will improve the drugs produced by the laboratory and increase the treatment potential for patients with neurodegenerative diseases.
If insoluble forms Fe3+ ions (Fe2O3) are generated by the permanent ROS, Fe2O3 are not active ions structures submitted to MHD only free ions, in the case of BBB process (in-out [elimination]). One makes the difference between IONIC forms of atoms An+ (room temperature) and ionized states A, I, II, III and experiment temperature associated to radiative emissions and transfers. Associated to Saha-Boltzmann equations of Thermal Equilibriums LTE-NLTE-PLTE temperatures 900 K to 30′000 K and more IV. Ions (H+, (D+[H—H]+), Fe2+, Ca2+, Zn2+, Mg2+, Ln3+ . . . ) can be elected to MHD-MGD processes, as atomic species seeded in the plasma state for chemistry-physics consideration (LTE-PLTE-NLTE).
Cyclodextrins-polymerized forms, Hb, ZnFLNT4, (other cyclic molecules (aromatics), can be elected to MHD-MGD, synthetic cyclic, nanoparticles NP and PP pico-particles- (destinated to Neuro Space Research).
The association of the four compounds inside the product SiHR57-01, -02, -03 (protocols), (NanoP-Pico-P) particles (molecules), and/or atoms are used in order to pass through or diffused within the BBB and clean the barrier and reach neuronal tissues organization and dissolve the Aβ plaques and ROS residues (different routes are proposed for the drug route, included nose to brain (N2B)).
The active molecules of the compositions are elucidated with NMR, GC-MS, and/or LC-MS spectroscopy tools.
The first mission of clean-up of the synaptic cleft interface mediators and dissolution and degradation of Aß amyloid plaques, T tau proteins (self-assembly or polymerized structures and degraded form), prions, tangles and PrP fragments, hemosiderin degraded, copper oxide, and APOEε[4] species in the cortex and hippocampus areas, others, re-activation of the connection area reconstruction of the synaptic network, and neurons nodes and poly-matrix organizations, transformation of astrocytes pool in mature neurons, reconstruction by the mean of pluripotent (master) stem cells and under magnetic B permanent or pulsed and electro-magnetic vectors, as well as Magneto-Hydro Dynamics MHD (
Elucidation and evaluation of the possible MGD (Magneto-Gas-Dynamics) applied on Hydrogen atom and bonds to Nitrogen-and in nucleic bases RNA-DNA. Hydrogen bonds at (steady state kinetics), LTE (Local Thermal Equilibrium), PLTE (Partial Local Thermal Equilibrium states) and NLTE (Non-Local Thermal Equilibrium).
In Alzheimer Disease as shown in NMRi images, it's trivial to pay attention of the neurodegenerative process, water is lost and healthy proteins are associated to lysis of functional tissues, the degraded proteins will increase the degenerative process, with more Aβ plaques, fragments, and ROS entropy, prions and loss of constitution water (linked to tissues), and losses in tissues structures lysis (gray-white matter); as illustrated in
The more important mission is to hydrate the brain at the standard level (balance), with the possible help of protocols SiHR57—the water level in tissues can easily be determine by NMR and/or MRI imaging with informatic adapted programs. SiHR57 can contain Na+, K+, or Li+ ions (formula of Silicon Compound [(CH3)3Si2(OH)3—R(COOX)], X can be Na3. K3, Li3) and R represents O, O2, OH—C3H4, Sodium silicate, Potassium silicate or Lithium silicate. This can assist in the regeneration of damaged neuronal tissue by STEM cells acting on astrocytes which will stimulate restoration of damaged neural tissue.
Mode of administration of the disclosed composition(s): oral, N2B (nose to brain), intranasal sprays (aerosols), dermic probes, trans-dermal patches, intravenous, intraperitoneally, intracranial. Active molecules administered by means of an intracranial probe are conveyed by means of a controlled-rate syringe, the conduit of the syringe can be subjected to permanent fields B around or solenoids in a pulsed or oscillating mode whose intensity varies from 0.05 Tesla at 0.3 Tesla (the Tesla value can be changed regarding the stage of the pathology and imagery control 1.5 T-3 T). This stimulation allows a preliminary alignment of the spins (atoms) and/or active ions.
Haemoglobin molecules, cyclodextrins, ursodeoxycholic acid, Zn-FLNT4 and part of depolymerized Aβ all under spin alignments, are subject to MHD-MGD properties.
Removal by circulation-diffusion (when dissolved) of toxic molecule(s) including but not limited to: plaques, tangles and prions and cholesterol, hemosiderin, Copper Oxide, and others as known to the skilled artisan as a result of dissolution and elimination via an external route at one or more of the BBB—by the means of solvents, under magnetic B vectors, MHD-MGD protons in membranes (transportation of toxic molecules and ions out of the BBB and brain tissues), and RF-EM collateral vector.
Reconstruction protocols of neuronal tissue: Use of pluripotent stem cells (stem cells) allows the future transformation of astrocytes into new neurons, the reconstruction protocol can be engaged only after the treatment of toxic molecules, fragments and plaques as represented in protocol SiHR57 01-02.
The potential for reconstruction using astrocytes and/or glial (glial cells) under the influence of stem cells and SiHR57 protocols is considerable, 5.1012 glial cells compared with 109 neurons. We can liken a neuron to a hard disk that can no longer retrocede memory files for lack of correct passwords (neuro-chemical and elementary mediators (metals and metalloids) and steady radiation (UV) and magnetic fields vectors are to be considered as the observables and solutions of the Hamiltonian matrix. The dopaminergic reconstruction is therefore complex but understandable, it seems that the nuclei memory extra-nuclei of neuron is associated with an electromagnetic memory.
All these chemical and biological considerations make it possible to construct a coherent set of drug vectors adapted to particular phases of the pathologies (see the protocols and combinations of formulas SiliconHR57), but also to better understand the chemical and molecular vector associations and physical (MGD-MHD, EM radiation, UV/Lasers, pulsed magnetic fields B). The associated or separate use of these vectors makes it possible to treat the origins, causes and consequences of these molecular pathologies.
In pharmacodynamics and pharmacokinetics approaches, the important notions of magneto-susceptibility (complex molecules and natural elements) that make up future agents or therapeutic vectors are not sufficiently considered at today. This vision and consideration of the magneto-susceptibility affects the entire biological environment, which is not static, because biology is living, but our tools of investigation are somewhat insufficient for the moment.
The water molecule plays a preponderant role in all the biological and biophysical phenomena of which the MHD-MGD presents within membranes including in synaptic clefts, ion transport and ion solvation. Water in our biology mainly in membranes could be assimilated as H2O monomer, because could adopt different degrees of polymerization n(H2O) due to the presence of weak UV radiation in biological membranes (5-10-50 nm). We can consider water as the first quantum liquid and hold a quantum, but also comparable to a gas mM 18 and subject to MHD-MGD principles under precise conditions in the context of Hamiltonian systems.
MHD-MGD mechanisms associated with the solvation of ions H3O+ protonation of the medium creates kinetics that oppose the residual entropy, especially in the aggregates of Aβ proteins, APOE, within the synaptic medium, to the extent that it can be considered analogous to fibrinogen monomers and also a quasi-polymerized form.
In the problems at hand, it is considered that the protective and/or therapeutic vectors must possess a powerful action of dissolution of toxic compounds molecules and part of molecules (plaques, fibrinogen, prions, fragments).
The present approach considers mechanisms of dissolution and elimination of toxic proteins and collateral products engaged in ROS, cholesterol LDL bound to others molecules, hemosiderin-copper (prions, fragments, PrP-plaques-tangles Aβ-APOEε4-tau proteins, self-assembly or polymerized structures and degraded form) and the reconstruction of neural brain organization with astrocytes and master stem cells—methods and protocols SiliconHR57-SiHR57™ (01 to −04) and strategies under RF-EM pulsed electromagnetic fields and permanent fields or solenoids (pulsed)—and under NMR 1.5 T to 3 T-and permanent 0.050 T to 0.1 T or pulsed or oscillating field Ferromagnetic species metals and Lanthanides as metals. T values can be changed and adapted to several routes for the drug SiHR57-included, but not limited to, endonasal, N2B-intracranial, intravenous-oral as known to one of skill in the art.
The present approach considers the use of Zn-FLNT4 (Zinc CARBONYL (ZNCO) cyclic formula Zn associated with D-Fructose molecule on C=O Carbonyl Radical (patent) (used as solvent) ZnFLNT4 (cyclic molecule) associated to Zinc (patent) as main solvent of toxic molecules associated to the degenerative process engaged in AD, Aβ plaques and prion fragments, Tau proteins (self-assembly CHO and/or polymerized structures and degraded form), APOEε[4], degraded hemosiderin, degraded ZnFLNT4, cyclic Electrochemistry process-Zn concentration 400 mg/L to 8000 mg/L used in protocols. Si element concentration for Liquids 300 mg/L to 3500 mg/L and for gels 20,000 mg/L used in protocols.
The present approach considers the use of silicon compound ((CH3)3Si2(OH)3—R(COOX)) wherein X can be Na, K, Li (hepato-neuro protector) and R represents O, O2, OH—C3H4, Sodium silicate, Potassium silicate or Lithium silicate. Germanium or other tetravalent element as well as SULFUR S32 can be used in place of Silicon or Carbon or associated with the Silicon composition.
The present approach considers the use of cyclodextrin(s) associated to one or several Zn atoms (av 65.4 mass) forming the cage molecule of Cyclodextrin(s) (α 972-β 1135-γ 1297), wherein the most soluble in water is γ CD 23%. The cyclodextrin cage associated with Zn is elaborated with an electrochemical process in the presence of Zinc, D-Fructose and also can be prepared with labelled Zinc 70. The external surface of cyclodextrins, in cage or torus shape, can accept hydrophilic compounds as well as Zn Carbonyl or others natural elements. Silicon-germanium nano or pico-particles, or other natural elements (precious metals and the like, hydrophobic compounds) can be lodged on the inner surface of cyclodextrins, whether in cage or torus shape, whereby cyclodextrins can be considered nano-carriers or pico-carriers. Cyclodextrins are under MHD-MGD process-BBB under MHD ions) and MGD process (p+-(H+)) membranes (5 nm-8 nm). Synaptic cleft is under MHD-ions Ca2+ (and other divalent molecules) Zn2+ (mediators) and under MGD processes where H+ membranes undergo high velocities of about 106 ions/s−1. Astrocytes are under influence of MHD-MGD process and contribute to the standard DOP (difference of potential) in the BBB layers and membranes.
The process of the release of natural elements on the elected area (neuronal tissues) is quite complex, we can consider that the Cyclodextrins cage or torus in general will obey at MHD-MGD observables—in all cases we can establish the Hamiltonians H (Harmonic Oscillator) and observables engaged in the quantum response under (radiative vectors and EM RF vectors), takes place in the Quantum Discussion. In these specialized cases of polarization and depolarization the matrix will obey to the creation a′ and a annihilation operators (quantum mechanisms formalism). The polarization effect and depolarization effect will conduct and assume the binding and the release of the future active substances. RF EM selected waves length and frequencies will organize and will engage and leads to the “drug” delivery consequence.
The present approach considers the use of cyclodextrin(s) cages in presence of Ln3+ (lanthanides or Rare Earths) elaborated with electrochemical process in situ CD and (Ln3+/La—Nd—Lu among others/14 and Y (Yttrium and/or Sc) for NMR-fMRI imaging with the labelled element of Ln3+, Tc+3 (99m) Technetium or Gadolinium Gd3+ (in the NMR imaging (Neuro imaging and Cardiovascular coupling) while the drug SiHR57 is distributed in the via the (BBB) or others routes, the results are obtained online coupled (patient under NMR fMRI and under efficient drug)—the monitoring will be considered as powerful too in order to establish the best routes for the drug and the choice of doses and protocol (adapted to the grade or stage of the pathology) AD and CVD Cardio Vascular Disease with the preliminary stage of Cardio Vascular Inflammation, and neuro immune deficiency, route N2B seems to be the more interesting clinical and investigation method. The concentration of cyclodextrins will be different depending the route of the drug and the solubility chosen SiHR57, 30 mg to 3000 mg. Lanthanides (Rare Earths) can be prepared under MHD-MGD tools.
The present approach considers the use of experimental physics concepts, such as the application of a MHD-MGD system to compositions, compounds and/or biological molecules or chemicals vectors, with the capabilities to constitute a cage shape, potentially as a toroidal construct, with aliphatic and/or aromatic compounds. MHD-MGD can be applied to cyclodextrins-oses, polyoses-phenols and polyphenols, molecules of haemoglobin (and BBB as physical shape (tube or sphere envelope) with heme structures circulating, creating a magnetic field outside of BBB by Fe+2 displacement of iron ions inside the BBB efflux. Glycans, proteoglycans and glycoproteins can be submitted under MHD-MGD process. The present approach considers the use of the silicon compositions described herein as nano-particles (
With an average molecular weight of 94 mi to 134 mi, SiHR57 molecules according to the formula ((CH3)3Si2(OH)3—R(COOX)) (with X as one of Na, K or Li), R represents O, O2, OH—C3H4, Sodium silicate, Potassium silicate or Lithium silicate and can easily pass through the BBB into CNS. This property is considered to explain the results obtained in both in vitro and in vivo tests performed by the Faculty of Pharmacology of the University Complutense of Madrid (UCM) with SILICON G57 in 2015.
The present approach considers the use of the plasma-based MHD-MGD process (
This applied research will be of high interest in deep space or micro gravity laboratories. High energy radiation such as γ and X rays, and other particles from solar activity and from deep space origin can easily interfere with DNA-RNA-nucleic bases and telomers and car damage seriously the structure. SiHR57 protocols can be used to supply the compositions, or functional food supplements including the composition, to astronauts for short or long trips in the solar system and beyond, likewise for medium to long residence at extra-terrestrial locations, in order to avoid the neurodegenerative situations. The modification of some nucleic base with substitution of Carbon atoms with Silicon or Germanium or Sulphur atoms can create a biologic shield: The Silicon or Germanium will absorb the radiation and will generate electric current flux; we can consider this phenomenon as negentropic. The loss of electric capability in our biology and structures can be considered as entropic situation. In particular conditions the current conditions can excite Silicon/Germanium crystals and the Si and Ge will emit EM radiation mainly UV (Ultra Violet). This phenomenon in DNA at low level of energy, will help the neural activities (clefts-and BBB—CNS) and the rebuilding of neural tissues with master stem cells and astrocytes.
The use of MHD-MGD at several orbitals LEO-NEO-GTO and deep space conditions is favorable due of the natural existing high vacuum 10−13 torr to 10−17 torr confirms the interest to engage experiments in Orbital Spatial Stations near Earth or Moon(s). The Nano P field can be used in space medicine (micro gravity) orbital Spatial Station or Nano, Pico or Femto gravity (deep space) and precisely for cancer research and DNA-telomers rebuilding. In addition, the Nano-P program can be associated to SN1-SN2 CRISPER Cas9 gene editing (sequencing) in order to protect DNA and telomers from solar radiation or cosmic radiation.
The species Nano-P and Pico-P is using a CD(s) carrier and Zn-FLNT4 (Zinc CARBONYL (ZNCO) (d-fructose) or other organic compounds and other metals. The NANO-P are trapped in the Cyclodextrins cage with the help of EM waves field of polarization selected by the lab, the release of the drug will be engaged with depolarization EM waves field—while the destination of the drug is verified by NMRi imaging. The elaboration of [Nano-, Pico-] P will be utilized in order for rebuilding the DNA proteins—and telomers—by sequencing engineering CRISPER cas9 as is known to one of skill in the art. The protocols might be used in the chelation of low-radioactive compounds by molecular cages among others, including but not limited to, Cyclodextrins.
Nano-P are fully active if the ROS has been decreased at the lowest level, the protocol SiHR57 can be associated to Nano-P treatment, mainly in cancerology (brain tumors, astrocytomes). The protocols SiHR57 can be associated with other protocols as well as radiotherapy and immunotherapies. Cyclodextrins can be used in electrochemical processes as described in WO/1996/023089, which is hereby incorporated by reference.
The present approach considers the use of the SiHR57 compositions, protocols and the pathologic molecules compounds and plasma tools described in the protocols for preparing new tools in biologic analysis including a quantum electro-magnetophoretic apparatus intended for research or routine biological analysis. A known tool includes an electrophoretic apparatus with two-dimensional spectral image (film) or plate or screen of proteins displayed, the new tool develops 3D spectral image (animation), included the affected area and will avoid errors or uncertainties on results.
The molecules are analysed under magnetic fields B (permanent-pulsed)/EM field and provide spectral analysis (magnetic gradient of response). This quantum tool is different from NMR analysis laboratory tool, the concerned molecules are spread on plates which are submitted to B-EM vectors, results are delivered in 3D images and not in 2 D images as well known in the classical electrophoretic analysis. The quantum tool will be able to detect the default of the molecular structure of proteins and part of proteins and will instruct the biologist where to use drugs or genetic tools (gene sequencing). Thus, valid molecules, under magnetic field deliver quantum calibrated responses (health value-opposed to unknown or pathological values).
Evaluation of the neuroprotective activity of Silicon HR57 within an active composition is conducted through in vitro and in vivo tests.
For in vitro tests, the Acetylcholinesterase (AChE) activity is determined spectrophotometrically by the Ellman method (Ellman et al., 1961) modified by Froede and Wilson (1984).
β-secretase activity is carried out by cleavage in Leu-Asp of a specific peptide for the β-secretase to finally produce a fluorescent signal, which is proportional to the degree of hydrolysis of the peptide substrate, and therefore, to the enzymatic β-secretase activity. Recombinant human-secretase (Sigma-Aldrich) and a fluorogenic substrate is used. Fluorescence is measured using a fluorescence reader for multi-well plates (Ni et al., 2013).
The determination of γ-secretase activity is based on the excision of a specific peptide for the γ-secretase to produce a fluorescent signal. The intensity of the fluorimetric signal is proportional to the degree of hydrolysis of the peptide substrate in Val-Ile-Ala, and therefore, to the γ-secretase enzyme activity. The aspartyl protease complex of γ-secretase is prepared from the membrane isolation of APPswe cells (Esler et al., 2002).
For in vitro fibrillogenesis of β-amyloid peptide, it has been proposed that the Aß peptide (25-35) represents the biologically active region of peptide 1-42, since it is the shortest fragment showing a conformational transition from a soluble form to an aggregated fibrillar form consisting of β-sheet structures and, that in addition maintains the toxicity of the full-length peptide (Pike et al., 1995). For this reason, the fragment 25-35 is used in this study. A simplified model of in vitro fibrillogenesis is established from a commercial peptide (25-35) in the monomeric form in solution that is incubated at 37° C. in a humid atmosphere for a period of 96 hours and with constant agitation (Stine et al., 2003). The process of in vitro fibrillogenesis under the influence of SiIHR57 is both qualitatively and quantitatively evaluated.
Qualitative evaluation is carried out by transmission electron microscopy. Quantitative evaluation uses a fluorimetric test of both the stationary and the resolved phases. The determination of the lifetimes allows the identification of potential inhibitors of the βA peptide aggregation and/or disaggregation. The variation in the fluorescence half-life due to the presence of SiHR57 allows quantification both of the inhibition of the βA peptide aggregation and of its disaggregation level.
The purpose of this experiment was to exemplify transformation of astrocytes in active neuronal tissue. Work done by Corti et al. has provided proof of concept that human cortical astrocytes can be converted into neural stem/precursor cells using a single stem transcription factor. (Corti, S., et al., “Direct reprogramming of human astrocytes into neural stem cells and neurons,” Ex. Cell Res. (2012 Aug. 1) 318 (13-16): 1528-1541, doi: 10.1016/j.yexcr.2012.02.040, PMID: 22426197, incorporated by reference.
The delivery of medications and therapeutics to the hippocampus or through the BBB via intra nasal and endo nasal administration are proposed, The objective is to achieve targeted administration and avoid systemic, adverse effects when treating patients suffering from AD, accumulation of polymers, plaques, dementia, Parkinson's disease and other neuro-degenerative diseases. Methods and results are described in Huang, Q. et al., “Research progress in brain-targeted nasal drug delivery” 2024 Front. Aging Neurosci., Sec. Neuroinflammation and Neuropathy 15:2023, https://doi.org/10.3389/fnagi.2023.1341295; Jeong, S-H., et al., “Drug delivery to the brain via the nasal route of administration: exploration of key targets and major consideration factors,” 2023 J. Pharm. Investig. 53 (1): 119-152, doi: 10.1007/s40005-022-00589-5; Handa, M. et al., “Potential of particle size less than 15 nm via olfactory region for direct brain delivery via intranasal route,” 2022 Health Sciences Review 4:100038. https://doi.org/10.1016/j.hsr.2022.100038; and Formica, M. L. et al., “On a highway to the brain: A review on nose-to-brain drug delivery using nanoparticles,” 2022 Applied Materials Today 29:10163. https://doi.org/10.1016/j.apmt.2022.101631, each of which are incorporated by reference herein.
The purpose of this experiment is to describe the dissolution of hemosiderin molecules located in the synaptic cleft and membranes within the “brains” of AD patients.
The addition of a chelation agent added to the saline solution used in WLL can include, but is not limited to, one or more of DEFERIPRONE (DFP), DESFERIOAMINE (DFO) and DEFERASIROX (DFX) and can be administered as an intranasal or nose to brain administration to act to chelate the hemosiderin, breaking it up/dissolving so that it is eliminate from the AD patient's brain.
The protocols are designed with the consideration that in Alzheimer's Disease AD, one of possible stages of the ROS stress process generates hemosiderin, cholesterol polymers within lung alveolar tissue which leads to death of the AD patient having been provoked by stroke including, but not limited to, cardio-stroke and/or pulmonary stroke.
ROS toxic products damage silently and accumulated in alveolar structures of AD patients over many years. Thus, we are proposing using WLL protocols, for AD patients, depending of the AD stage, as determined by the physician to reverse within pulmonary tissues the toxic bi-products and side effects of ROS toxicity as well as reverse brain ROS toxicity.
Applicant notes that for each drug (listed below) added in the LAVAGE saline solution (or other mode of administration) the physician is aware of the CAS number and adversarial effects of the compounds, and only use routine concentrations for the WWL lavage. In considering the possible intake drug protocol (routine drug administration will be calculated on the basis of the pharma vigilance notice delivered by the manufacturer). And, if one drug was administrated by oral or intranasal or via intravenous or via intraperitoneal the physician will appreciate the corresponding concentration used will be different than that used in the WLL.
Possible drugs list: LAVAGE LIQUID compounds or routes of administration:
This makes use of a treated lavage solution that will cross the BBB due to blood's contiguous circulation to not only preclude delivery to the brain of ROS toxic products including, but not limited to, toxic molecular wastes as well as porphyrin among others, aluminium, hemosiderin, APO, and degraded polymers of cholesterol. Such an approach is taken with the consideration that ROX toxic products appear in neuro-degenerative processes similar to a neurotoxic retroviral infection similar to the way COVID-19, a retrovirus, is addressed by WLL. Therefore, proposed is a new route to the mitigation, prevention and treatment, including WLL, dialysis or ECMO mechanical action to support Oxygen enrichment within the AD patient's lungs and so to within the brain as blood carries the treated lavage components through the BBB and to the brain serves as an effective mechanical and physiochemically competent way to circumvent ROS toxicities.
The following WLL protocol to clean the lung alveolar structures can be viewed as an Engineering Protocol to provide the Proof Of Concept (POC) to be confirmed in patients (more than 500 patients) who are either intubated and/or experiencing sever pulmonary stress. The removal of toxic products, hemosiderin and cholesterol will be assayed via Immune Assays of the CSF (Cerebral Spinal Fluid, G1200 CSF) to be analysed in bio immune machines developed by Fuji Rebio and in Blood immune assay developed by several laboratories, all known to the skilled artisan, in order to verify one or more of the level of APOE contamination by tangles and plaques in AD (Alzheimer pathology) at different stages. (early AD-to final AD stages) to evaluate SiHR57.
This is a mechanical action via use of the WLL (physics-saline solution dynamics chemistry incorporating sodium heparin (only if compatible with the biochemistry clinically presented data to the neuro-degenerative (including AD) patient. It is noted that to add or exclude in the WLL procedure, Sodium Heparin, regarding the patient's clinical chemistry of their Iron status and Sodium status among others. The Sodium heparin will probably help in the Protocol.
The first action is to clean the Alveolar structures mechanically via WLL.
Chosen is a chelation agent added to the saline solution can include, but is not limited to, one or more of DEFERIPRONE (DFP), DESFERIOAMINE (DFO) and DEFERASIROX (DFX).
Drugs added to the saline solution include, but are not limited to CYCLODEXTRIN (molecular cage form to be elected,
Alveolar structures can be damaged due to contaminants, agents resulting from the ROS induced by toxic molecules or viral genes. Added to the saline solution can include, but are not limited to, Zinc citrate/Zinc carbonyl, OrthoSilicic acid (Silanol compound)-SiHR57-Silicone G57.
Possible Associated protocols to Protocol Action Cycles 1 through 4:
Use of ECMO for extra corporal oxygenation and/or ECTR dialysis for removal of CO2 and other toxic compounds.
This experiment describes a method for preparation of organometallic complexes in which a water-soluble organic compound having a carbonyl function is complexed with a metal using electrosynthesis. The method is further described in WO1996/023089 A1 which is incorporated by reference herein in its entirety.
The water-soluble organic compound having a carbonyl function in a solution is placed in a vessel (5 Litres or greater) containing a water bath and two metal electrodes connected to an electric current source and immersed in the water solution and between which an electric voltage is applied, the anode is made of the metal, for example, Zinc, to be complexed on the organic compound, for example, D-Fructose molecule on C=O Carbonyl radical (Zinc Carbonyl) and associated with a silicon compound CH6NaO3Si or (CH3Si2(OH)3—R(COOX)), wherein X can be sodium (Na), potassium (K) or Lithium (Li) and R represents O, O2, OH—C3H4, Sodium silicate, Potassium silicate or Lithium silicate. Thus, the method makes it possible to carry out, in particular, the complexion of aliphatic or hemicyclic oses, pepyoses, co-enzymes, amino acids, proteins, chemical mediators, neurotransmitters, hormones, vitamins, nucleic acids, oligosaccharides, in the presence of metal electrodes. An oxidizing gas such as oxygen is sent into the solution. Tests have shown that when a voltage is applied between the two electrodes of the tank, the metal of the anode passes into solution and is fixed to the carbonyl group of the organic compound.
The solution can consist of the organic compound having a carbonyl function solubilized in water of sugars (C5, C6 and C8) and more generally of form (C6), but also polyoses (C6) j and to complexing them by electrosynthesis with metals (or natural elements). The sugars used have a ketone or carbonyl site function (C═O). This carbonyl function, such as in fructose, is associated with other alcohol or aldehyde groups. The method in its installation aims to fix a metal or several elements (Se, Zn) electrochemically on the carbonyl site, aldehyde and more rarely on the alcohol function. This metal or natural element associated with the structure may have valences greater than 1. Exceptionally, the monovalent elements (Na, Li) may be associated with anodic alloys in order to allow their release in the aqueous medium. Other alkali or alkaline-earth elements including but not limited to, Ba, Ca, Sr may also be associated with anodic alloys.
Trimethyl Silane Triol can be elaborated from Sodium or Potassium Silicate, pH13-14 basic and Citric acid H+. Combining K2SiO3+Citric acid will form a gel: Trimethyl Silane Triol: [(CH3) 3 Si (OH) 3] CH2-COOK—COH—COOK-CH2-COOK potassium base which is soluble in excess Citric acid.
The DC voltage imposed on the terminals varies from 10 to 220 volts and the intensity may vary from 0.3 to several tens of amperes for more bulky tanks. The spacing of the electrodes varies from 0.5 cm to several centimetres for a 5-litre tank, one anode is of the same nature as the metal to move and to complex. Since fructose is reducing, variable (sugar/water) ratios where used as well as an external supply of pure oxygen or air, a few litres per minute, to prevent the Fe (ose) form from predominating on the Fe (ic) form.
The temperature of the bath must be maintained between 20° C. and 50° C. in order to avoid rapid oxidation of the complex formed Fe3+ ic or Fe2+ ose. The bath can accommodate moderate stirring. The concentration of the metal is a function of the criteria of imposed electrolysis and of the time imparted to the electrosynthesis. The products formed are considerably stable even for Fe (ose) under the condition of preserving it in the absence of Heat and Bright Light and preserved in bottles or good glass appears to be better.
The concentrations (Fe2+, Fe3+) obtained vary from a few mg/L to a few g/L
The sugar/water ratios are as follows:
In order to obtain a Fe2+ complex (without outside Oxygen) 300 g of sugar/1000 g of water, this ratio may be variable. The addition of Oxygen also allows for better homogenization of the electrolytic medium and counteracts the reduction by the sugar. Complementary experiments were conducted with other divalent or trivalent or tetravalent metals. They form stable complexes with fructose and generally with other oses. The complexed metals were as follows: Cu: 439 mg/l, Zn: 500 mg/l, Co: 90 mg/l, Nr: 80 mg/l, Fe: 1300 mg/l, V: 300 mg/l, mg: 600 mg/l, Sb: 50 mg/l, Al: 10 mg/l, Ag: 30 mg/l. Metalloids: C, Se, semiconductors: Ge, Si, and lanthanides more particularly: Tm: 173 mg/L, Lu: 170 mg/L, Yb: 300 mg/L, La: 150 mg/L, Gd: 70 mg/L, Nd: 100 mg/L. It seems that all the metals may be complex to an ose or a polyose using the electrosynthesis process described. The method can also use alloyed anodes composed of elements such as Na, K, Ca, Ba, Sr, Se. This method exceptionally allows these elements to participate in the complexing mechanisms. The same method can be used for semiconductors.
This experiment describes a preparation of an Antibiotic-metallic complex in which a water-soluble antibiotic compound having a carbonyl function is complexed with a metal using electrosynthesis.
The method for forming an antibiotic-metallic complex follows the method of Experiment V and is described for several antibiotics:
Streptomycin derived from a trans-saccharide, possessing an aldehyde function CHO with the carbonyl group C=O allows the complexing with the natural elements of anodic origin.
Chloramphenicol The presence of a carbonyl group C=O allows the complexing with metals of anodic origin.
Novobiocin The presence of a carbonyl group and a peptide bond [CONH] on a heterocycle allows good complexion of novobiocin with natural elements of anodic origin.
Tetracycline The presence of 3 carbonyl groups allows very good complexion with the natural elements of anodic origin.
Penicillin Penicillin is an example of a peptide substance having two carbonyl groups allowing a complexion with metals or elements of anodic origin.
Gramicidin S and oxytocin also possessing several carbonyl groups to allow 30 complexing using the process.
Rhythromycin and rifamycin may also make it possible to form metalocomplexes with the process.
Biotic and therapeutic consequences of the complexions formed
The antibiotics are considered as specific inhibitors which can cause side effects, some patients are intolerant to these molecules. Erythromycin, tetracycline, chloramptenicol, rifamycin are acting as RNA synthetase inhibitors, while blocking the mitoses of bacterial or viral agents, can also cause side effects and can lower immune defences when administered intensively. The complexing method makes it possible to release, in the protein and enzymatic mediums, the metals and natural elements depleted by the antibiotic reaction.
For in vivo tests, testing SiHR57 in the APPswe cell line allows for the selection of a non-toxic concentration range of this product (Mosmann, 1983); for the examination of the potential neuroprotective effect of SiHR57 by determining the inhibition of free radicals generated from exposing the cells to hydrogen peroxide (Garcimartin et al., 2014).
Next is the BV2 cell line, derived from murine neonatal microglia, which is frequently used as an alternative of primary microglia, because it has certain advantages related to difficulties in maintaining adequate cell culture and functionality (Blasi et al., 1990). This cell line helps determine how SiHR57 modifies nitrite release after activation with interferon INFγ (Chow et al., 2012). The determination of nitrites, as stable metabolites of NO, is carried out in BV2 cells activated with interferon INFγ. The quantification of these metabolites is carried out using the colorimetric method based on the Griess reaction. This reaction is based on the formation of a chromophore by the reaction of sulfanilamide with nitrite in an acid medium, followed by a coupling. NO-2 reacts with sulfanilamide in an acid medium producing a diazo compound, which subsequently, through a coupling reaction with N−1-(naphthyl) ethylenediamine, gives rise to a purple azo compound. 2) Neuroprotective effect of SILICON HR57 against inflammation stimulated by LPS in microglial cells BV2 and determination of free radicals (Cai et al., 2018).
By way of statistical analysis, data is processed using the statistical package SPSS (statistical package for social sciences), version 25.0. The mean and standard error of the individual values obtained for the samples of the animals of each group is determined. Normality distribution of data is determined, using parametric or nonparametric test when data normalization would be unavailable. The analysis of variance (ANOVA) or the multiple comparison test of Kruskal Wallis, followed by the adequate post-hoc test, is used to compare values obtained from different groups and treatment. A multivariant test (e.g. MANOVA) is also applied, wherein P values <0.05 is considered significant.
The SiHR57 study is initiated in a model of experimental Alzheimer's. The mouse transgenic line Tg2576 (B6; SJL-Tg (APPSWE) 2576Kha) is selected, heterozygous “knock-in” line, which carries the hAPP with the Swedish double mutation of Alzheimer's disease (K670N, M671L) that favours the action of the γ-secretase instead of the α-secretase, giving rise to accumulations of Aß in the brain, either diffusely or forming plaques. These deposits begin approximately at 9-12 months of age of the animals. They also present cognitive deficits, learning and spatial memory, damage by free radical action, oxidative stress and apoptosis.
The in vivo tests aim to evaluate the general motor activity of Tg2576 mice at 18 months of age, after having been chronically exposed to a dose of an aggressive agent (e.g. 1 mg Aluminium/g of diet and 3.2% of citric acid) and the effect of Silicon HR57 compositions thereon, and to evaluate whether Silicon HR57 compositions can modify the concentration of Aβ in the cortex and hippocampus of Tg2576 mice.
The total number of animals at the beginning of the study is at least 100 (50 wild-type and 50 Tg), with genotyping at 4 weeks. The number of deaths stipulated by the house is 33%.
Reagents used for in vivo experiments include: For the treatment of animals, standard maintenance diet (Panlab), diet supplemented with aluminium lactate and citric acid (1 mg Al/g of diet and 32 g of citric acid/Kg of diet) (Harlan); for genotyping, Tris Base (2-Amino-2-hydroxymethyl-propane-1,3-diol) (Sigma), EDTA (Sigma), SDS (Sodium dodecyl sulfate) (Sigma), Proteinase K (Sigma) and sodium chloride ethanol; for the sacrifice of animals, Ketamine hydrochloride, 100 mg/ml, Xylazine hydrochloride 20 mg/ml; for the determination of accumulated Aß, AEBSF (4-(2-aminoethyl)-benzene sulfonyl fluoride) (Sigma), Guanidine hydrochloride (Sigma), Potassium chloride (KCl) (Sigma), Basic sodium phosphate (Na2HPO4) (Sigma), Acid potassium phosphate (KH2PO4) (Sigma), Sodium hydrogen carbonate (NaHCO3) (Merck), Human Aß40 ELISA kit KMB3481 (Invitrogen), Human Aß42 ELISA kit KMB3441 (Invitrogen), Bradford reagent (Sigma), Bovine serum albumin (BSA) (Sigma).
Devices or apparatuses used for in vivo experiments include: for genotyping, a source of electrophoresis, a thermocycler, an Image Master VDS; for behavioural tests, an open field (OF), a Morris Water maze, a video camera and computer software. For the detection and analysis of the movement of animals in the OF and in the Water maze, the video camera is coupled to a computer configured for use with the Etho-Vision program; for the determination of Aß fragments, a spectrophotometer plate, an ELISA kit for Aβ(1-40), A⊕(1-42) and Aβ(25-35).
The compound and techniques described above find further application in respect of pathologies arising from contamination by the COVID-19 virus. We can consider the biodegradation of pulmonary embolism and toxic molecules produced similar to (CVA) Cardio Vascular Accident and Ischemic Stroke (AIS): in the case of COVID-19, the toxic molecules are among others hemosiderin and bio-degraded fragments of the COVID-19 genome sequence. Dechelation agents can be used, and mainly applied to hemosiderin with deferiprone (DFP), desferioxamine (DFO) and deferasirox (DFX) compounds or sodium heparine.
Hemosiderin is the logical molecular consequence of the biodegradation of haemoglobin. Hemosiderin constitutes the main barrier to oxygen exchanges in the pulmonary alveolar functions and creates clots, blocking the oxygen chain supply to eventually cause patient death. We can consider the pathologic results in the PAP and PE as the direct action of the viruses involved in reactive oxidative stress (ROS), causing strong oxidation and peroxidation of the blood compounds and thus generating the hemosiderin, among others.
We can logically conclude that this oxidative stress produces polymers of cholesterol and protein plaques similarly to Alzheimer's Disease. Thus, it is logical to consider use of the DFP-DFO-DFX chemical compound in the Alzheimer Disease protocol, for solubilizing bio-degraded hemosiderin compounds.
In terms of procedure, the patient should undergo the whole lungs lavage (WLL) protocol as described in “Whole lung lavage—technical details, challenges and management of complications” by Ahmed Awab, Muhammad S. Khan, and Houssein A. Youness in J Thorac Dis. 2017 June; 9 (6): 1697-1706 (doi: 10.21037/jtd.2017.04.10, PMCID: PMC5506114, PMID: 28740686), pursuant to a medicinal decision based on a double opinion, after a biological survey and control parameters have been established to determine how WLL should be applied to the patient, including any counter indications against DFP-DFO-DFX for the patient under these molecules.
A biologist should preferably collect a patient sample before, during and after WLL treatment, to determine and then monitor bio-chemical compatibility and toxicity of the drugs, together with the correct dosage according to the specific patient and their admission status at either intensive care or reanimation stage. Several CT scans of the patient at pulmonary level should preferably also be carried out at least before and after the WLL procedure, but also during the WLL procedure if resources allow.
Additional active compounds may be used either during the WLL procedure, or thereafter, in addition to the DFP-DFO-DFX compound, such as Hydroxy Chloro-Quine (HCQ), Sodium Heparin (if compatible with the biochemistry clinic data of the patient), Cyclodextrin (form to be elected), antibiotics (notably azithromycin among other antibiotics as described in international patent application WO1996/023089 A1) as well as zinc salts such as Zinc citrate, Zinc Carbonyl, ZnFLNT4 a Zn-Carbonyl compound, and ortho-silicic-acid, Ursodeoxycholic acid, OrthoSilicic Acid (Silanol compound), SiHR57, Azithromycin, or (CH3)3Si2(OH3)3—R[CH2—COONa]3 and R represents Sodium silicate, Potassium silicate or Lithium silicate, or OH—C3H4, O, O2, in order to protect alveolar functions.
The invention is not limited to the embodiments hereinbefore described but may be varied in both construction and detail. In the specification the terms “comprise, comprises, comprised and comprising” or any variation thereof and the terms include, includes, included and including” or any variation thereof are considered to be totally interchangeable and they should all be afforded the widest possible interpretation and reciprocally.
All publications, references, patents, and patent applications mentioned in this document are herein incorporated by reference to the same extent as if each individual publication, reference, patent, or patent application was specifically and individually indicated to be incorporated by reference. Publications, references, patents, and patent applications are detailed in U.S. Provisional Patent Application No. 62/878,558
There follows a list of acronyms used in the present disclosure for ease of reference:
| Number | Date | Country | Kind |
|---|---|---|---|
| LU101272 | Jun 2019 | LU | national |
| S20200056 | Apr 2020 | IE | national |
This application is a Continuation-In-Part of U.S. patent application Ser. No. 16/906,450, filed 19 Jun. 2020, which claims the benefit of priority to each of U.S. Provisional Application No. 62/878,558, filed 25 Jul. 2019, Luxembourg Patent Application No. LU101272, filed 19 Jun. 2019 and Ireland Patent Application No. IES20200056, filed 7 Apr. 2020, each of which are hereby incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62878558 | Jul 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16906450 | Jun 2020 | US |
| Child | 18651665 | US |
