GB2600668A - Alpha Lipoic Acid (A-ALA) and Alpha Lipoic Acid (R-ALA) As a Pharmaceutical Product for Intravenous Application to reduce Inflammation from infection. - Google Patents

Abstract

A natural powerful anti-oxidant and anti-inflammatory that has access to every cell and organ in the body. Alpha lipoic acid may reduce inflammation in the lungs of a COVID-19 infected patient.

Description

DESCRIPTION

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1. Alpha Lipoic Acid (A-ALA) and Alpha Lipoic Acid (R-ALA) As a Pharmaceutical Product for Intravenous Application to Reduce Inflammation from infection. To repair nerve damage

Background Description

Lipoic Scientific Name(s): 2-dithieiane-9-penlaneih acid. 1,2.2.:thic,k:ii':;:c.2.-Wiikale. acid, 5-fl vaieric acid, 6,8-thioclic acid Comman Narne(s). Acalate tdohia-ii.arAc acid; Eietan, Lipoc add, Lipeicin, hioctie arad lhioctic ao:d Or 4..1,,ac acid. Alpha I pacacc scr a yeiow onsiaiizod aooearanea. and is nalwaihi:tuned with in the mannoncsria ri rida'a: amounts. a a an Cggal:::"; C.Caapaala also found in iealy green vecciabies and red meat Lipoic cod (dithiolane-3-pentanoic acid: thioctic acid) is an eight carbon acid with two suithydryi grottos in positions 6 and 8, a low molecular weight of 206 g/ trioi, and both hydrophilic and iipophilic properties. it is a potent redox active compound with a negative midpoint redox ootential of -0 29 V and has an important function in energy metaboiism (LA) and its reduced term. dyarclipoio acid. are pia:yea-La aailexidor9 scuve:ig;3a hydroxyi radicMs, hypohniercaio acid, paroxyrffl:Oti.:.:, and saiciiat oxycler. ipThydrfl5peiC SCA also scavenges a:peroxide and oarrooa radicals and can regenerate ti-doredox;n, vitamin C, and caidathiono, which in;urn can recycle vitamin E. In. It:a a coenzyme with character:shoe that inciude etticient antioxidants with the capacity to regenerate endogenous antioxidants such as glutathlone, vitamin C. and vitamin E with potentlei therapeutic properties in the treatment of metal-induced oxidative stress it is an essential for aerobic metabolism and a naturally occurring disulfide compound, (A-ALA) acts as a cellular coenzyme and has been applied for the treatment of polyneuropathies and hepatic disorders. Has capabilities to enhance intraceliular giutathione (GSH) levels. Normalize the oxidative stress induced by Dexamethasone in chicken. studies on the effects of ALA on nicotine damaged lungs and hypoxia have had positive results.

IV. ALA was isolated by Reed ia 1951 ii as an acetate aap:acinci taethr and as firsi. chnical L:Se dates from 1959.

Alpha-lipoic acid a sulphurous acid, naturally occurring compound, synthesized in the mitochondria. it is a organosulfur compound derivative of octanoic (Caorylic) acid. it:a present in food and is synthesized by the liver. It is a natural cofactor in the pyruvate cle.hydrogenase compiex, where it binds acyl groups and transfers them from one hart of the complex to another. Some reported application of this compound has been seen for treatment of cancer HIV and liver ailments. The antioxidant properties of alpha-I:pi:sic acid have been linked to several benefits, including lower blood sugar levels, reduced inflammation and antioxidant properties.

2. CHEMICAL NAME Synonyms: C8 H.14 0282 lipoic acid 1200-22-2 (R)-lipcic acid R-(+)-alpha-Lipoic acid (R)-5-(1,2-Dithiolan-3-Apentanoic acid (A-Lipoic Acid) and (R-Lipoic Acid) Summary of Benefits and Properties Third party studies found ALA Water and fat soluble which gives it access to every cell and tissue in the body Regenerates Vitamin C (water soluble) and enhances production of vitamin E (fat soluble) Operates inside the mitochondria to assist enzyme conversion of glucose.

Increases intracellular glutathione and regenerates ascorbic acid, vitamin E, coenzyme Q10, and nicofinamide, adenine dinucleotide phosphate. It acts synergistically with insulin, lowering blood glucose, increasing liver olycogenesis, and facilitating glucose uptake into cells.

Improves measures of glucose utilization in metabolic disorders such as diabetes.

Approved in Germany for the treatment of diabetic nerve pain and numbness (IV and oral administration alpha-lipoic acid can improve the function and conduction of neurons in diabetes.

AMPK activities: AMPK is an important enzyme invoived in cell energy arid metabolism /(ALA) * Increases AMP-activated protein kinase (AMPK) in blood vessel and muscle cells.

* Reduces AMPK in hypothalamus when combined with ACE inhibitors reduces high blood pressure.

s Reduces activity of AMPK in the hypothalamus (activated protein kinase (AMPK) and may increase number of calories the body burns at rest 4.

* Thus it may have a slight affect of weight loss, * Contrastingly, If there is a very active (AMPK) ALA may cause feelings of hunger.

Cofactor for mitochondrial multienzyme complexes. Two cofactors are in the citric acid cycle, assisting various organisms turn nutrients into energy.

Boosts energy.

Boosts the immune system by scavenging ROS (reactive oxygen species) Boosts levels of natural antioxidants (e.g., glutathione and manganese superoxide disrmitase Antioxidant properties smooths muscle reducing skin ageing, in R-(ALA) potent intracellular antioxidant properties that can induce all three cellular protective mechanisms.

mitochondrial protective mechanisms, direct antioxidant protection, enhancement of GSH-dependent intracellular defences Promotes healthy nerve function Helps reduce scar tissue in the brain after a stroke key role in metabolism and energy production.

functions as an antioxidant, protecting your cells from damage and helping restore levels of other antioxidants. C Nit E) by reducing the levels of oxidized stress Lowers heart disease risk factors Platelet effects: Lowers activation of platelets that contribute to inflammation in blood vessels. (iv.87, 92) Suppresses excess platelet production. (iv.92) Inhibits platelets from sticking to blood vessel wails(which can build plague and clog arteries). (iv.92) Roosts production of nitric oxide. (NO). (iv.88, 93) A-(ALA) antioxidant properties reduce production of impaired Nitric Oxide (NO)-mediated vasodilation in diabetes has been attributed to increased vascular oxidative stress.

Inhibits inflammatory immune system response to plaque in arteries (such as increased levels of T-cells help prevent the development of diabetes and obesity which are both risk factors for heart disease by reducing damage from free radicals in the liver.

Improves blood vessel function by reducing nigh levels of ADMA Asymmetric dimethylarginine (ADMA) a molecule similar to the amino acid arginine, normally found in blood plasma Inhibits heart tissue cell death following heart attack and return of blood flow Special Benefits Water and fat soluble giving access to every cell and organ in the body. No pro-inflammatory properties.

How A-(Al:" and RjALA Work on the inflammatoi s stern.

Inflammatory response Overexpression of ACE2 ameliorates A13-induced inflammatory response by activating the ACE2/Ang-(1-7)/Mas axis in human RPE cells. ACE2/Ang-(1-7) AMD.

is located mainly in the capillaries of the lungs but can also be found in endothelial and kidney epithelial cells. A-(ALA) and R-(ALA) act as inhibitors of the inflammatory activation signalling process by binding to ACE2.

A new important component of the RAS is the type 2 angiotensin-converting enzyme (ACE2) a homolog of ACE, can cleave ANG land ANG II to ANG-(1-9) and ANG-(1-7), respectively. ANG-(1-7), the product of ANG II degradation by ACE2, has opposite properties to that of ANG II, by acting on the Mas receptor (MasR). The ACE2-ANG-(1-7)-MasR axis of the RAS promotes vasodilation, antiproliferation, and reduction of heart failure ACE2 is a membrane protein that can undergo shedding to release a catalytically active ectodomain from the cell surface in the extracellular milieu (2$). The proteases involved in this process are called sheddases, and they control the biological activity of membrane proteins. A well-known sheddase is a disintegrin and metalloproteinase 17 (ADAM17), also c:Jiiezt necJ<JJ:k It was hypothesized in this third party study that chronic RAS activation enhances oxidative stress and ADAM17 activity thus promoting ACE2 shedding. Antioxidant, A-lipoic acid (LA) decreased oxidative stress and downregulate ADAM17 expression. LA, exists in both R-and S-enantiomeric forms. In the study only (R)-LA was conjugated to conserved lysine residues in an amide linkage, thus making this isofonn essential as a cofactor in biological systems. It documented that LA reduces BP and improves baroreflex sensitivity in renovascular hypertensive rats, the mechanisms underlying these effects remain unknown. To address this, we used Neuro2A cells (neuroblastoma cell line) and an experimental model of neurogenic hypertension combining chronic administration of deoxycorticosterone acetate (DOCA), reduced renal mass, and a high-salt diet (DOCA-salt model) The role of Renin in the Kidney is to catalyses the conversion of the plasma glycoprotein angiotensinogen to angiotensin. (ACE2). The renin-angiotensin system ( RAS), or reninangiotensin-aldosterone system ( RAAS), is a hormone system that regulates blood pressure and fluid and electrolyte balance, as well as systemic vascular resistance. When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor prorenin (already present in the blood) into renin and secrete it directly into circulation.

Effects of adipoic acid on LPS-induced neuroinflammation and NLRP3 inflammasome activation through the regulation of BV-2 microglial cells activation (the resident rnacrcu:aaes of the central nervous system (e c.'). The (,:elis are a orlmary form of active immune defence in the CNS.

This third party study, aimed to investigate the anti-inflammatory effects of a-LA in relation to its regulatory role on several inflammatory responses and NLRP3 inflammasome activation through increased M2 phenotype.

Study investigated the effect of a-LA on the inflammatory response in lipopolysaccharide (LPS)-treated BV-2 microglial cells. Our results revealed that a-LA significantly attenuated several inflammatory responses in BV-2 microglial cells, including pro-inflammatory cytokines, such as to necrosis factor-a and interleulen (li")-6, and other cytotoxic molecules, such as nitric oxide and reactive oxygen. In addition, a-LA inhibited the LPS-induced phosphorylation of ERK and p38 and its pharmacological properties were facilitated via the inhibition of the nuclear factor kappa B signaling pathway. Moreover, a-LA suppressed the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes, multiprotein complexes consisting of NLRP3 and caspase-1, which are involved in the innate immune response. Finally, a-LA decreased the genes accountable for the M1 phenotype, IL-1p and ICAM1, whereas it increased the genes responsible for the M2 phenotype, MRC1 and ARG1. These findings suggest that a-LA alleviates the neuroinflammatory response by regulating microglial polarization.

ALA decreased pro-inflammatory cytokines ri LPS-induced BV-2 mic.rogilal cells Cytotoxicity of a-LA was evaluated prior to the analysis of pro-inflammatory cytokines in BV-2 cells. Cells were incubated with a-LA (100, 200, 500, and 1000 RIM), with or without LPS (1 pg/m1), for 24 h. a-LA did not present cytotoxicity at any of the concentrations employed (Fig. 1A). These results suggest that a-LA did not affect the viability of BV-2 cells in vitro. To further analyze the effects of a-LA on pro-inflammatory cytokines production, BV-2 cells were incubated with both the indicated concentration of a-LA and LPS. Although both TNF-a and IL-6 levels were found to be increased in LPS-induced BV-2 cells, their expression was considerably decreased in a-LA treated BV-2 cells (Fig, 18 and C). These results suggest that a-LA inhibits the production of pro-inflammatory cytokines without affecting cell viability.

Previous studies have reported that the activation of NF--KB mediates the activation of NLRP3 inflammasomes in microglia (4), which induces pro-caspase-1 cleavage. While western blot analysis tiontonstraK:d NILRP3.: acth,p caspase-1 were markedly increased in response to LPS stimulation, treatment with a-LA significantly reduced their LPS-induced protein expression when compared to those in control cells (Fig. 3D). This indicated that a-LA, not only reduces the immune response associated with NF-kB signaling, but also decreased NLRP3 inflammasome activation.

In summary, the study suggested that a-LA both reduces NLRP3 inflammasome activation, NF-x13, MAPK signaling, and pro-inflammatory cytokine release in LPS-induced BV-2 microglial cells and modulates microglial cells M1/M2 polarization. Although the mechanism underlying the regulation of NLRP3 inflammasome activation by microglial cells polarization is yet to be fully elucidated, the study indicates that a-LA may represent a candidate drug for the treatment of both inflammatory and chronic neurodegenerative diseases In a study of osteoarthritis 78 patients were divided with half the patients randomly selected to receive a daily dosage of A-(ALA). Before and after treatment, visual analogue scale (VAS) and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores were determined. The levels of interleukin-1p (IL-113), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), interleukin-17 (1L-17) and interleukin-23 (1L-23) in serum were measured using enzyme-linked immunosorbent assay. After treatment, the VAS pain score and WOMAC function score of the patients in the a-lipoic acid group levels of IL-113 were significantly lower than those in the control group The levels of IL-1p (P<0.001), IL-6 (P<0.05), TNF-a (P<0.001), IL-17 (P<0.001), and IL-23 (P<0.01) in the serum of patients treated with a-lipoic acid after treatment were also significantly lower.

The research found that A-(ALA) reduced the level of inflammation, which may be associated to the inhibition of TLR4/NF-KB and IL-23/1L-17 signaling pathways, IL-17 and its upstream regulatory factor IL-23 can promote the secretion of inflammatory factors such as IL-1P, IL-6 and TNF-a increasing the pathological progress of inflammatory diseases. The secretion of TNF-a and other inflammatory factors in the lung, heart, aorta and other tissues are also reduced by a-Lipoic Acd.

http:ii vmsw. ijcern. cornifil es/II cem0082 'I 1 1. pdf of which interleukin-6 (1L-6), tumor necrosis factor-a (TNF-a) was also reduced.

Another study found that Crystalline silica and asbestos are known to activate the NLRP3 inflammasome, implicating its role in the pathogenesis of silicosis and asbestosis [15-17]. Aluminium salt (alum) can also activate the NLRP3 inflammasome, albeit in the presence of PAMPs such as LPS [17-19].

Summary

Key Words._ACE2 -sheddases -metalloproteinase 17 (ADAM17) -(inflammation) A-(Lipoic Acid) A-(ALA) inhibits activation of pro inflammatory cytokines by inhibiting activation of the signaling process of (1L-23/17) that upregulates (IL-6) in the inflammatory response to infection. In doig so it prevents ACE2 shedding and activation of ADAM 17 and NOD like receptor protein NLPR3, a key player in the inflammatory response. And signaling pathways.

A-(ALA) Decreased pro-inflammatory cytokines in LPS-induced BV-2 microglial cells Suppresses the activation of NF-k13 (NLRP3) inflammasomes.

Mediated the activation of NLRP3 inflammasomes in microglia which induces pro-caspase-1 cleavage.

Inhibited NLRP3 (TLR4/NF-KB) activation of NOD-like receptor pyrin domain 3 (NLRP3) Inhibited the nuclear factor kappa B inflammatory signaling pathway.

Prevented the secretion by inflammatory factor (IL-17) up regulation of (IL-6) Inhibited ACE2 shedding inflammatory reaction signalling process to ADAM 17 (TNF-a) Reduced inflammation in endothelial and kidney epithelial cells.

Improved blood cell viability Improved heart function.

Metabolism and Bioavailability Endocienous biosynthesis The synthesis of lipoic acid has been characterized in detail in the yeast Saccharomyces cerevisiae, but not all genes involved in the process have been identified in humans fj.).. Lipoic acid is synthesized de ROW in mitochondria from octanoic acid, an 8-carbon fatty acid (C8:0), bound to the acyl-carrier protein (ACP; see article on Pantothenic Acid) during the process of fatty acid synthesis (Figure 2). An enzyme called lipoyl (octanoyl) transferase 2 catalyzes the transfer of the octanoyl moiety from octanoyl-ACP to a conserved lysine of the H protein of the glycine cleavage system (see also Biological Activities). The next reaction is the insertion of two sulfur atoms at positions 6 and 8 of the protein H-bound octanoyl moiety, thereby producing a dihydrolipoyl moiety. This step is catalyzed by the lipoic acid synthetase (also called lipoyl synthase), an enzyme containing iron-sulfur clusters that act as sulfur donors in the reaction (5). Finally, the enzyme lipoyl transferase 1 catalyzes the transfer of the dihydrolipoyl moiety from the H protein of the glycine cleavage system to conserved lysine residues of the E2 components of the a-ketoacid dehydrogenase multienzyme complexes (51. The oxidation of the dihydrolipoyl moiety is catalyzed by a dihydrolipoamide dehydrogenase.

Scavenging reactive oxygen and nitrogen species: Reactive oxygen species (ROS) and reactive nitroge., jp:s_ti:esjsi_s (RNS) are highly reactive compounds with the potential to damage DNA, proteins, and lipids in cell membranes. Both lipoic acid and dihydrolipoic acid can directly scavenge (neutralize) physiologically relevant ROS and RNS in the test tube (reviewed in 3). However, whether direct quenching reactions occur in vivo is unknown. The highest tissue concentrations of free lipoic acid likely to be achieved through oral supplementation are at least 10 times lower than those of other intracellular antioxidants, such as vitamin C and glutathione. Moreover, free lipoic acid is rapidly eliminated from cells, so any increases in direct radical scavenging activity are unlikely to be sustained.

Regeneration of other antioxidants: When an antioxidant scavenges a free radical it becomes oxidized itself and is not able to scavenge additional ROS or RNS until it has been reduced. In the test tube, dihydrolipoic acid is a potent reducing agent with the capacity to reduce the oxidized forms of several important antioxidants, including coenzvme Qio vitamin C and glutathione (Figure 5) C 6, 17.). Dihydrolipoic acid may also reduce the oxidized form of a-tocopherol (vitamin F.) directly or indirectly through regenerating oxidized vitamin C (see the article on Vitamin E) (1S) or oxidized coenzyme Qt0 (see the article on Coenzvme Qt.) (19) Whether dihydrolipoic acid effectively regenerates antioxidants under physiological conditions is unclear (3).

Metal chelation: Redox-active metal ions such as free iron and cooper, can induce oxidative damage by catalyzing reactions that generate highly reactive free radicals f20). Compounds that chelate free metal ions in a way that prevents them from generating free radicals offer promise in the treatment of neurodegeneratiye diseases and other chronic diseases in which metal-induced oxidative damage may play a pathogenic role (21). Both lipoic acid and dihydrolipoic acid have been found to inhibit copper-and iron-mediated oxidative damage in the test tube (22,23) and to inhibit excess iron and copper accumulation in animal models (24. 25). Lipoic acid may also be helpful as an adjunct treatment against heavy metal toxicity. No clinical trial has examined the use of lipoic acid as a chelating agent in mercury toxicity, yet it has proven to be effective in several mammalian species 126 27).

Activation of antioxidant signaling pathways: Glatathione is an important intracellular antioxidant that also plays a role in the detoxification and elimination of potential carcinogens and toxins. Reductions in glutathione synthesis and tissue glutathione concentrations in aged animals (compared to younger ones) are suggestive of a potentially lower ability to respond to oxidative stress or toxin exposure (28). Lipoic acid has been found to increase glutathione concentrations in cultured cells and in the tissues of aged animals fed lipoic acid (29., 30). Lipoic acid might be able to increase glutathione synthesis in aged rats by up-regulating the expression of y-glutamylcysteine ligase (y-GCL), the rate-limiting enzyme in glutathione synthesis 5,31', and by increasing cellular uptake of cysteine, an amino acid required for glutathione synthesis (32). Lipoic acid was found to upregulate the expression of y-GCL and other antioxidant enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway ci in.

Briefly, Nr12 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keapl) in the evtosol. Keapl responds to oxidative stress signals by freeing Nrt2. Upon release, Nrf2 translocates to the nucleus where it can bind to the antioxidant response element (ARE) located in the promoter region of genes coding for antioxidant enzymes and scavengers. Lipoic acid but not dihydrolipoic acid can react with specific sulfhydryl residues of Keapl, causing the release of Nrf2 (34). Nrf2/ARE target genes code for several mediators of the antioxidant response, including y-GCL, NAD(P)H quinone oxidoreductase 1 (NO0-1), heme oxygenase-1 (H0-1), catalase, and superoxide dismutase (SOD). For example, the upregulation of the Nrf2 pathway by lipoic acid in cultured hepatocytes and in the liver of obese or diabetic rats prevented lipid overload-induced steatosis (35) and cell death (36). Lipoic acid also protected liver from oxidative stress-induced liver injury in methotrexate-treated rats through the activation of Nrf-2 pathway and other anti-inflammatory pathways (37). Pre-treatment and post-treatment with lipoic acid, respectively, prevented and reversed lipopolysaccharide (LPS)-induced lipopolysaccharide in rats through Nrf2-mediated HO-I upregulation (38).

ocpclysact a * PS), is a main consttuent of Gram-negative bacteria: membrane have been used to thesis arid secretion of towth tprontoting foe/arts such sis inter:eukins and ecificaily °Mike receptor 4, iceding to the production of pkeioti cytokitiesichetttaknes which n n:eau:ate infiarnmatotv and innate and subsequent adaot mime resoonses in Diabetes risk or infection is;ncreased by risk of inflammation.

In another study applying lipopolysaccharide (LPS) stimulation as a model for bacterial infection, results indicated that LPS significantly increased the expression of toll-like receptor (TLR) 2/4 pathway-related genes and pro-inflammatory factors Diabetes The effect of high-dose lipoic acid on gint.4"se, utilization has been primarily examined in individuals with type 2 diabetes. An early clinical trial in 13 patients with type 2 diabetes found that a single1ptrayenc3us. infusion of 1,000 mg of lipoic acid improved insul1n-stimulated glucose disposal (i.e., ins: sensitivity) by 50% compared to a placebo infusion A placebo-controlled study of 72 patients with type 2 diabetes found that oral administration of lipoic acid at doses of 600 mg/day, 1,200 mg/day or 1,800 mg/day improved insulin sensitivity by 25% after four weeks of treatment 08). There were no significant differences among the three doses of lipoic acid, suggesting that 600 mg/day may be the maximum effective doselfjcS). However, in a more recent randomized, placebo-controlled study in 102 subjects, daily supplementation with 600 mg of lipoic acid (+/-800 mg of vitamin E [a-tocopherol]) for 16 weeks had no effect on fasting blood glucose, fasting blood insulin, or a measure of insulin resistance called the homeostatic model assessment of insulin resistance (1OMA-IR) index ($9). A 2018 systematic review and meta-analysis identified 20 ranclonn zed controlled trials (published between 2007 and 2017) that examined the effect of supplemental lipoic acid on markers of glucose utilization in 1,245 subjects with metabolic disorders (not limited to type 2 diabetes) 0122. Administration of lipoic acid (200 to 1,800 mg/day for 2 weeks to 1 year), alone or together with other nutrients, was found to lower fasting blood glucose and insulin concentrations, insulin resistance, and blood HbAlc concentration a marker of glycemic control over the past few months t, Endothelial function The inner lining of blood vessels, known as the vascular endothelium, plays an important role in the maintenance of cardi ovascul a r health. In particular, nitric oxide (NO) regulates vascular tone and blood flow by promoting the relaxation of all types of blood vessels, including arteries a phenomenon called vasodilatian. Alterations in NO-mediated endothelium-dependent vasodilation results in widespread vasoconstriction and coagulation abnormalities and is considered to be an early step in the development of atherosclerosis. The presence of chronic hyperglycemia, insulin resistance, oxidative stress, and pro-inflammatory mechanisms contribute to endothelial dysfunction in patients with diabetes mellitus (6 The measurement of brachial flow-mediated dilation (FMD) is often used as a surrogate marker of endothelial function. Two techniques are being used to measure endothelium-dependent vasodilation. One technique measures the forearm blood flow by venous occlusion plethysmography during infusion of acetylcholine. Using this invasive technique, intraarterial infusion of lipoic acid was found to improve endothelium-dependent vasodilation in 39 subjects with type 2 diabetes but not in 11 healthy controls C6 2). A more recent randomized, placebo-controlled study in 30 patients with type 2 diabetes found that intravenous infusion of 600 mg of lipoic acid improved the response to the endothelium-dependent vasodilator acetylcholine but not to the endothelium-independent vasodilator, glycerol trinitrate CO3'1. Another noninvasive technique using ultrasound to measure flow-mediated vasodilation was used in two additional studies conducted by Xiang et al. 164 65 The results of these randomized, placebo-controlled studies showed that intravenous lipoic acid could improve endothelial function in patients with impaired fasting glucose (64) or impaired glucose tolerance (63).

One randomized placebo-controlled trial that assessed the effect of oral lipoic acid supplementation in 58 patients diagnosed with metabolic syndrome a condition characterized by abnormal glucose and lipid metabolism, showed that flow-mediated vasodilation improved by 44% with 300 mg/day of lipoic acid for four weeks (50.

Diabetic neuropathy Peripheral neuropathy: Up to 50% of diabetic patients develop peripheral neurcipathv, a type of nerve damage that may result in pain, loss of sensation, and weakness, particularly in the lower extremities (671. Peripheral neuropathy is also a leading cause of lower limb amputation in diabetic patients (6S). Several mechanisms have been proposed to explain chronic hvoerglyeemia-induced nerve damage, such as intracellular accumulation of sorbitol, glycation reactions, and oxidative and nitrosative stress (reviewed in 69). The results of several large randomized controlled trials indicated that maintaining blood glucose at near normal concentrations was the most important step in limiting the risk of diabetic neuropathy and lower extremity amputation (70-72). However, evidence of the efficacy of enhanced control of glycemia in preventing neuropathy is stronger in patients with type 1 diabetes than in those with type 2 diabetes (731 Moreover, this glucose control intervention increased the risk of hypoglycemic episodes (773'.

The efficacy of lipoic acid, administered either intravenously or orally, in the management of neuropathic symptoms has been examined in patients with diabetes. Meta-analyses of randomized controlled trials suggest that infusion of 300 to 600 mg/day of lipoic acid for two to four weeks significantly reduced the symptoms of diabetic neuropathy to a clinically meaningful degree (55 74). Regarding the efficacy of oral lipoic acid supplementation, an initial short-term study in 24 patients with type 2 diabetes mellitus found that the symptoms of peripheral neuropathy improved in those who took 600 mg of lipoic acid three times a day for three weeks compared to those who took a placebo (73). A larger clinical trial randomly assigned more than 500 patients with type 2 diabetes and symptomatic peripheral neuropathy to one of the following treatments: (i) 600 mg/day of intravenous lipoic acid for three weeks followed by 1,800 mg/day of oral lipoic acid for six months, (ii) 600 mg/day of intravenous lipoic acid for three weeks followed by oral placebo for six months, or (iii) intravenous placebo for three weeks followed by oral placebo for six months (70. Evidence of improvements in sensory and motor deficits assessed by physicians could be observed after three weeks of intravenous lipoic acid therapy, yet not at the end of six months of oral lipoic acid therapy. However, another randomized, double-blind, placebo-controlled trial in 181 patients with diabetic neuropathy found that oral supplementation with either 600 mg/day, 1,200 mg/day, or 1,800 mg/day of lipoic acid for five weeks significantly improved neuropathic symptoms f 77). In this study, the 600 mg/day dose was as effective as the higher doses. Finally, a four-year, multicenter, clinical trial in 421 diabetic patients with distal symmetric sensorimotor polyneuropathy found no difference between oral administration of 600 mg/day of lipoic and placebo on the primary endpoint, a composite score that assessed neuropathic impairment of the lower limbs and nerve conduction (78) Yet, measures of specific neuropathic impairments (secondary outcomes) improved with lipoic acid supplementation (78). A post-hoc analysis suggested that oral lipoic acid supplementation may reduce neuropathic symptoms particularly in subjects with a high burden of cardloyascolar disease diabetes, and neuropathy yet with normal both mass index (B1\41) and blood pressure (1.21.

Autonomic neuropathy: Another neuropathic complication of diabetes mellitus is cardiac autonomic neuropathy (CAN), which occurs in as many as 25% of diabetic patients (55). CAN is characterized by damage to the nerve fibers that innervate the heart and blood vessels, leading to reduced heart rate variability (variability in the time interval between heartbeats) and increased risk of mortality (SO). In a randomized controlled trial of 72 patients with type 2 diabetes and reduced heart rate variability, oral supplementation with 800 mg/day of lipoic acid for four months resulted in significant improvement in two out of four measures of heart rate variability compared to placebo (81).

Summary: Overall, the available research suggests that treatment with intravenous or oral lipoic acid may help reduce symptoms of diabetic peripheral neuropathy. The use of lipoic acid is currently approved for the treatment of diabetic neuropathy in Germany (4). It is important to note that many of the studies that examined the efficacy of lipoic acid in the treatment of diabetic neuropathy have been primarily conducted by one German research group and funded by the manufacturer of lipoic acid in Germany (82).

Diabetic retinopathy Chronic hyperglycemia can damage blood vessels in the retina and cause a potentially sight-threatening condition called diabetic retinopathy L83). One placebo-controlled study examined the effect of lipoic acid on the visual capability of 80 participants of whom 12 had type 1 diabetes, 48 had type 2 diabetes, and 20 were diabetes-free. The result showed that daily oral administration of 300 mg of lipoic acid for three months prevented the deterioration of contrast sensitivity in patients with diabetes and improved it in healthy patients compared to placebo (84) Adverse effects In general, high-dose lipoic acid administration has been found to have few serious side effects. Intravenous administration of lipoic acid at doses of 600 mg/day for three weeks 2) and oral lipoic acid at doses as high as 1,800 mg/day for six months an) and 1,200 mg/day for two years (76) did not result in serious adverse effects when used to treat diabetic perinheral neuropathy. There was no significant difference in the incidence of adverse events and serious adverse events in patients with diabetic neuropathy who took 600 mg/day of lipoic acid for four years compared to those in the placebo group (78). Oral intake of 2,400 mg/day for two weeks was also found to be safe in a pilot study that included participants with multiple sclerosis Two mild anaphylacioid reactions and one severe anaphylactic reaction, including laryngospasm, were reported after intravenous lipoic acid administration ( 55). The most frequently reported side effects of oral lipoic acid supplementation are allergic reactions affecting the skin, including rashes, hives, and itching. Abdominal pain, nausea, vomiting, diarrhea, and vertigo have also been reported, and one trial found that the incidence of nausea, vomiting, and vertigo was dose-dependent (77). Further, malodorous urine has been noted by people taking 1,200 mg/day of lipoic acid orally (95).

DYPSNEA

There has been one reported case of Dypsnea Pregnancy and lactation A retrospective observational study reported that daily oral supplementation with 600 mg of lipoic acid (raCelOiC mixture) during pregnancy and without interruption from a period spanning between week 10 and week 30 of gestation and until the end of week 37 was not associated with any adverse effect in mothers and their newborns (114). In absence of further evidence, lipoic acid supplementation during pregnancy should only be considered under strict medical supervision. The safety of lipoic acid supplements in lactating women has not been established and should thus be discouraged (1151.

Children A case of intoxication was reported in a 20-month old child (10.5 kg bw) after the accidental ingestion of four 600-mg tablets of lipoic acid (116). The child was admitted to hospital with seizure, acidosis, and unconsciousness. Symptomatic management and rapid elimination of lipoic acid led to a full recovery without sequelae within five days. The non-accidental ingestion of a very high dose of lipoic acid led to multi-organ failure and subsequent death of an adolescent girl 11171.

Drug interactions In theory, because lipoic acid supplementation may improve insulin-mediated tr. ucose utilization (see Diabetes mellitus), there is a potential risk ofiri.ofticernia in diabetic patients using insulin or oral anti-diabetic agents (I IS). Consequently, blood glucose concentrations should be monitored closely when lipoic acid supplementation is added to diabetes treatment regimens. Yet, one study in 24 healthy volunteers reported no significant drug interactions with the co-administration of a single oral dose of lipoic acid (600 mg) and the oral anti-diabetic agents, glyburide A Third party study shows that Alpha-lipoic acid alone and combined with clozapirte reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms study.

Alpha Lipoic Acid Side effects as listed by Everday Health are.low blood sugar--headache, hunger, weakness, sweating, confusion, irritability, dizziness, fast heart rate, or feeing jittery; or a light-headed feeling, like you might pass out.

Common side effects may include: nausea; or skin rash.

This is not a complete list of side effects COV0-19 COVID-19 is believed to originate from Bats, unaffected viral hosts of COVID-19,. The virus severely affects the Respiratory system, lungs, and organs. Recent research shows that entry to the human body is facilitated via TMPRSS via the Spike-S protein which them actives the inflammatory process via ACE2, ADAM-17 and NLPR3, resulting in inflammation of the lungs air-sacks and ACE2 which is also located within the lung tissue. Patients experience a lack of oxygen and difficulty breathing. Lungs are crystalized and become immovable. A high presence of Nitric Add, Nitric Oxide and Carbon dioxide is present by failure of the lungs to exhale the toxins The slow oxidation of carbon dioxide oxidation of carbohydrates delay glucose production and there-fore delay energy, conversion into fatty acids or reserve fatty acids, it is a cause kidney impairrnent and or liver inflammation, In Diabetes high triglycerides at factor in that raise risk of heart disease. Blood cells are abnormal and are already less oxygenated. Wth the excess (002), the respiratory system suffers more significantly than one with normal cell functions. The chemical reaction of 002 forms Carbonic acid when mixed with moisture and is exhaled from the lungs. In COVID-19, water is not drained efficiently from the lungs resulting in congestion and excess mucus. In non Diabetic patients COVID-19 also affects the cardio-vascular and respiratory system. This was reviewed in relation to Bats respiratory system.

Bats can hibernate for 6 months on a small amount of body fat, during which ti likely they become viral hosts of COVID-19. They inhale oxygen mixed with Nitric and Phosphorous Acid made from the mix of the guano gases, Uric Acid, Oxygen and Carbon dioxide or Carbonic Acid. The sustainable environment for the COVID-19 virus.

Guana (Bat poop) crawling with microorganisms, reaching up to 12 meters in height, produces the mix of Phosphorous and Nitric Acid. The Nitric oxide reacts with the hydroperoxy radical (H02.) forms nitrogen dioxide (NO2), which reacts with a hydroxyl radical (OH) to produce nitric acid (HNO3) While Nitric Oxide is part of the immune response anti vasodilator, increasing blood flow and lowering blood pressure. Generated by phagocytes. monocytes, macrophages and neutrophs. (NO) can cause irritation of the Respiratory Tract, and eye irritation, shortness of breath, dyspnea and breathing difficulties. There are similarities in symptoms from the disease caused by inhaling guano known as Histoplasrnosis or Cave disease, with to Covid19, which causes pneumonia, flu like illness and fever also. Bats bpm can go from 20bprn to 600bpm, there lungs are larger, which suggests that Bats exhale the virus when flying, and that whilst hibernating and ingesting the virus, the resting heart rate is fairly low which means minimum quantity of oxygen is mixed with the Nitric and Phosphorous acid, there-fore congestion from, and production of, Carbon dioxide is less likely to occur.

The rate of carbon dioxide (032) oxidation is lower than the rate of Nitric oxide oxidation which can also result in higher levels of carbon dioxide, (waste product.) and less oxygenated blood, breathing difficulties or tissue or organ damage. (002) has the function to metabolise fats, amino acids and carbohydrates in cellular respiration which makes it's presence also more relevant in the case of a diabetic patient affliction of COVID-19 because the low rate of conversion compared with the Nitric Oxide faster conversion rate, results in a high lingering quantity of (CO2).and Nitric Oxide, with poor circulation and less oxygenated blood cells which leads to nerve damage.

A dissimilarity is that patients severely afflicted with COVID-19 are often diabetic and obese, or obese. In contrast Bats hibernate with low body fat and are asymptomatic. This suggests that COVID-19 is ability to duplicate itself to the extent of severe respiratory illness, is dependant somewhat on Tryglicerides lipopolysaccharides, and glucose.

Bats also have an acidic PH between 4.5 to 5.5phand re asymptomatic. Patients with an acidic PH above 7.0 may be more affected simply due to already having an alkaline PH, when infected with the virus which may be acidic. H2CO3

Another symptom of COVID-19 is excessive water and mucus in the lungs.

A study found CO2 present in the blood combines with water to form carbonic acid. (a solution of carbon dioxide in water) which is then exhaled as a gas by the lungs. when there is too much carbonic acid the body increases rate and depth of respiration to reduce the co2, which reduces the carbonic acid,(water in the plasma + co2 = h2co3) when the co2 level goes down below normal levels, respirations slow and become more shallow to retain "n2 which increases the carbonic acid, and adjusts the blood PH. Exposure at high concentrations can irritate the eyes and respiratory tract. Water on the lungs (Pulmonary Edema,) is a symptom of Pneumonia, which is similar to the symptom in COVID-19. Research shows that Non-cardiogenic pulmonary edema can be caused by Acute respiratory distress syndrome (ARDS), a potentiaiiy serious coricbtion caused by severe infections, trauma, lung injury, inhalation of toxins; lung to the lungs. similar to that of CCiVlD..i9 effect on the lungs and eiffilfrialieS nitrogenous waste. ,s; cocaine smoking, or radiation A) re-oxygenates the air sacks

Claims (3)

1. CLAIMA natural powerful anti-oxidant, and anti-inflammatory said to have access to every cell and organ in the body. The third party studies seen here conclude that (ALA)-may reduce inflammation in the lungs in a COVID-19 infected patient.COVID-19 SYMPTOMS COVID-19 VIRUS UK Government information A(ALA)Study results Effective dosages Head ache has a layer offal powerful antioxidant lanti-inflammatory does in the Third party studies range from 300-600mg Temperature dies in 60d and soap and water available in every cell in the body because it is fact and water soluble. EVERYDAY HEALTHSIDE EFFECTSEverday Health are.low blood sugar--headache; hunger; weakness, sweatind, confusion; irritability, dizziness, fast heart rate; or feeling jittery; Or a light-headed feeling, like you might pacs out.Common side effects may include: nausea; or skin rash.This is not a complete list of side effects Dry Cough can live on cardboard and hard surfaces for various periods of time. short airborne life. facilities Vitamin D. Vitamin E and Glutathione.shortness of breath affects Diabetics Obese more than others repairs and oxygenates red blood cells. scavenges ROS. Rids the body of toxins, reduces inflammation in the I ungs difficulty breathing highly contagious inhibits ACE2 from becoming inflamed loss of taste or smell transmitted by touch of hand to mouth, nose Or eyes, sneezing, coughing, spitting, repairs nerve damage tiredness or feeling weak. Can affects the lungs; Muscle pain possibly has a low PH value around 4.5 ---5.5PH regulates and lowers blood sugar; Yellow eye fing can re-infect a person. Kidney Function Studies show that Alpha Lipoic Acid scavenges Reactive Oxygen Species, (ROS) with it's lower form dihydrolipoic acid ridding the body of toxins, reduces inflammation and oxygenates the blood cells, improving the level of oxygen in the lungs and circulation. Studies found that A-(/LA) reduced tingling, muscle pain and prickling feelings in the feet and legs. Production of Glutathione, a powerful anti-oxidant was enhanced by A-(ALA). Erectile Dysfunction is thought to be a condition of Diabetes, brought on by high blood sugar, nerve damage, and poor circulation. Once the symptoms of Diabetes desist with healthy oxygenated red blood cell flow, and regulation of the systemic PUS by scavenging and removing the toxins, so should the Erectile Dysfunction condition.Summary Alpha Lipoic AcidFrom the afore studies it appears that A-(ALA) and R-(ALA) is a potential Drug for COVID-19 and Diabetic COVID-19 and Erectile Dysfunction because it inhibits the enzyme 1"0E2 in the respiratory system which can become severely inflamed during infection with COVID-19, causing shortness of breath and difficulty breathing leading to the need for ventilator assisted breathing. Alpha Lipoic Acid lowers blood sugar levels, repairs nerve damage by re-oxygenation the cells, improving blood flow, and scavenging free radicals. Repairs nerve damaged blood vessels, reduces inflammation by inhibiting ACE2 in the lungs, preventing inflammatory responses, resulting in less oxidated stress, enhanced muscle and nerve function in ED, A-(ALA) is already approved for use in Diabetic Neuropathy in Germany.A-(Alpha Lipoic Acid) and R(Alpha Lipoic acid also assists in reduction of Diabetes by Lowering blood sugar Reversing neuropathic damage to cells.Regulating, repairing and oxygenating the blood cells which improves respiration.Creates energy in the mitochondria.Assisting Kidney function by scavenging (ROS) Reactive Oxygen Species Improving cardiovascular function by enhancing blood cells Slight weight loss in people with medium active AMK by ridding the body of the high tryglicerides (fat cells) and LDL (bad cholesterol).Reduces the production of Tryglicerides by regulating Blood PH and removal of waste produce.Assists the release of Vitamin 0 improving immunity to infection.Assists the generation of Vitamin E, (antioxidant) into the blood cells helping to protect cells from damage caused by free radicals, an high blood glucose levels.Acts synergistically with insulin, lowering blood glucose, increasing liver glycogenesis, and facilitating glucose uptake into cells.References I.Reil1951 1 as csaL. p:acnig Su Min Kim,1,# Ji Sun Ha,1,# A Reum Han,2 Sung-Woo Cho,2,* and Seung-Ju Yang1, Author information Article notes Copyright and License information Disclaimer Copyright © 2019 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.II. 2002 by: Jane Higdon, Ph.D.Linus Pauling Institute Oregon State University III. Citation: Wendel, J. (2015), How bat breath and guano can change the shapes of caves, Eos, 96, doi:10.1029/2015E0039053. Published on 9 November 2015 AMENDED CLAIMS HAVE BEEN FILED AS FOLLOWS:-CLAIMS1. Thioctic acid and its reduced form dihydrolipoic acid, works synergistically with adenin, thiamin,riboflavin, pantothenic acid and pyridoxine and has efficacy to attenuate the effects on the central nervous system, the respiratory, arterial and cardiovascular systems in severely affected Covid-19 patients and patients with 12DM.
2. 2. Thioctic acid and its reduced form dihydrolipoic acid, works synergistically with niacin, Adenin thiamin, riboflavin, Pantonthenic acid, and Inositol and has efficacy to attenuate the inflammatory effects on damage to the cardiovascular, arterial and central nervous system. Repurposing of thioctic and dihydrolipoic acid for use in the prevention of severe inflammatory cytokine response in the lungs of severely affected Covid-19 patients, Sars cov-2 patients and patients with type 2 Diabetic mellitus and obese patients, promotes vaccine efficacy.
3. 3. Thioctic acid and its reduced form dihydrolipoic acid, works synergistically with vitamin B complexes to attenuate the inflammatory and associated responses in the lungs, respiratory and cardiovascular system in Covid-19, Sars Cov2 associated illnesses including arterial thrombosis, and some cancers such as HIV and immunodeficiency illnesses. Repurposing vitamin B complex and both forms of thioctic acid promotes inhibition and prevention of the severity of the symptoms.