- Comfortably Numb - Pink Floyd | Kent Nishimura (in one guitar)
Latest posts made by Amazoniac
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RE: Resources for authors
"Open Knowledge Maps is a nonprofit organization that uses AI to help users discover and visualize scientific literature. Users can map a research topic, find documents, and identify concepts from various databases and sources."
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RE: Aspirin metabolism: glycine and beyond
The rationale was: carbon dioxide goes through cells' lipids and releases a proton inside once hydrated. Then, let's find another compound that's also not barred by lipids and releases even more protons. This led to 2,6-DHBA.
It overlooks that the very property that makes the selected compound a greater acidifier is also what makes it extraordinarily prone to deprotonate prematurely. The ability to pass through lipids is likely to be compromised with the early proton release. If it could be injected into the tumor, it would still be uncertain if it could be taken up by target cells.
Healthy Cancerous Extracellular pH 7.4 ↓6.5 Intracellular pH 7.1 ↑7.5 For direct internal acidification, it would be more fitting to seek weak rather than strong acids, those that can take advantage of the bump in transitioning from the extracellular to intracellular compartment (6.57.5) to deprotonate the molecule where intended.
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RE: Aspirin metabolism: glycine and beyond
A few issues concerning the salicylic acid analogue mentioned in this recent article.
Salicylic acid
- 2-hydroxybenzoic acid (2-HBA)
γ-Resorcylic acid
- 2,6-dihydroxybenzoic acid (2,6-DHBA)
Variations in the additional hydroxyl group relative to salicylic acid (orange):
Hydroxybenzoic acid isomers and the cardiovascular system
The coordination in 2,6-DHBA helps to stabilize the molecule in an ionized state:
Source: the internet.I think that this property is responsible for its lower pKa, making it a 'stronger' acid, that's more prone to deprotonate (benzoic acid → benzoate⁻ + H⁺) and stay as such.
pKa:
- 2-HBA: 3.0
- 2,6-DHBA: 1.3
This does make 2,6-DHBA a molecule with greater acidification potential. However, the pH in the body is much higher than needed to ionize them, making the difference irrelevant:
- 50 mmol 2-HBA → 50 H⁺ mmol
- 50 mmol 2,6-DHBA → 50 H⁺ mmol
Once we adjust their doses to match for their alleged potencies and possible risk of toxicity, we may get something like:
- 50 mmol 2-HBA → 50 mmol H⁺
- 5 mmol 2,6-DHBA → 5 mmol H⁺
Which casts doubt on the benefit being from relying on a 'stronger' acid.
To counteract the inverted pH of cancer cells, we have to acidify the interior or alkalinize the exterior. 2,6-DHBA deprotonates already in the stomach, which only adds to the burden of extratumoral acidification. In contrast, I just shared with Jennifer a clinic that infuses baking soda in people with cancer.
Ray's suggestion to manipulate acidity through carbonic anhydrases has more basis. The hydrocarbonate ion recirculates in cancer cells and functions as a carrier of protons, taking them from inside, discharging outside, and repeating the process. Inhibition of carbonic anhydrases compromises this removal of protons and creates an unfavorable environment in cells.
Regarding lipophilicity, the greater the degree of hydroxylation, the less lipophilic a molecule tends to be. It's what happens to venom D when it goes from kilciol to kilcidiol and then to kilcitriol.
"The obtained (experimental and theoretical) logP values for HBAs are in the range 0 < logP < 3; this means that these compounds possess from slightly hydrophilic (logP: 0–1) to moderately lipophilic properties (logP: 1–3) [101]. Generally, the disubstituted hydroxybenzoic acids were more lipophilic than the trisubstituted one (gallic acid has hydrophilic properties, and dissolves well in water and other polar solvents). According to the experimental logP values, the compounds can be ordered by increasing lipophilicity as follows: 3,4,5-THB→3,4-DHB~3,5-DHB→ 2,3-DHB→2,4-DHB →2,5-DHB →2,6-DHB."
"Dissociation and association phenomena affect the value of the partition coefficient. Therefore, we observed a relationship between the acid dissociation constants (expressed as pKa) and the values of partition coefficients. Each functional group that can be a hydrogen bond donor or acceptor increases the hydrophilic nature of the compound. Hydroxyl and carboxylic groups present in the structures of the compounds can form hydrogen bonds with water molecules in the aqueous environment, which affects their solubility in water. Therefore, in the case of 3,4,5-trihydroxybenzoic acid, an increase in the hydrophilic properties of the acid is noticeable. The more hydrogen bonds can be formed between a molecule and water molecules, the greater its solubility in water. In the case of ortho- substituted benzoates, the -OH group in the ortho- position is mostly engaged in hydrogen bond formation with the -COOH group, facilitating dissociation of the H+ carboxylic group and increasing the acidity of 2,6-DHB (pKa = 1.30) and, to a lesser extent, 2,3-DHB (pKa = 2.91), 2,5-DHB (pKa = 2.97), and 2,4-DHB (pKa = 3.11). In the case of 3,5-DHB (pKa = 4.04), 3,4-DHB (pKa = 4.26), and 3,4,5-THB (pKa = 4.40), the -OH groups are too far from -COOH to interact with this functional group, but may form hydrogen bonds with the solvent. As a result, the acidity of these acids decreases (higher values of pKa) compared to the ortho-substituted benzoates."
"The dependency between acidity (pKa exp.) and lipophilicity (logPexp.) in the series of studied hydroxybenzoic acids is shown in Figure 7. With the increase in the acidity of the compounds, the lipophilicity increases as well. Therefore, the hydroxybenzoic acids can be divided into three groups characterized by: (a) lower acidity and lipophilicity (3,4,5-THB; 3,4-DHB; 3,5-DHB), (b) moderate acidity and lipophilicity (2,3-DHB; 2,4-DHB; 2,5-DHB), and (c) higher acidity and lipophilicity (2,6-DHB)."
That's counterintuitive.
But here's the value for salicylic acid:
"Experimental n-octanol-water partition coefficients (logPexp) determined by traditional shake-flask method were equal to 2.35 and 1.14 for salicylic and acetylsalicylic acids, respectively."
Aspirin is 'rapidly deacetylated' in the body, and salicylate is the main circulating metabolite, which must not differ a lot from 2,6-DHBA in terms of lipophilicity.
Aspirin, stroke and drug-drug interactions
They don't include the small intestine in the first-pass effect, when it's also responsible for the presystemic metabolism of the drug.
Acetyl transference appears to be a neutral reaction. But deacetylation through hydrolysis leads to proton release rather than the expected consumption (to reform the hydroxyl group). A proton from a water molecule is taken up by salicylate and the rest complexes with the freed acetyl group, which occurs deprotonated.
Aspirin and salicylate: An old remedy with a new twist
"Aspirin has a short half-life in circulating blood (~20 minutes) and is rapidly deacetylated and converted to salicylate in vivo. Salicylate does not affect COX-1 or COX-2 activity. Thus, the anti-inflammatory and antineoplastic actions of aspirin and salicylate remain a dilemma. Sodium salicylate paradoxically inhibited prostaglandin synthesis when added to intact cells.[7] Furthermore, healthy subjects taking sodium salicylate excreted a significantly lower amount of prostaglandin metabolites in urine than those not taking sodium salicylate, and their levels of inhibition were comparable to those of patients taking aspirin and indomethacin.[9] Aspirin also reduces human seminal prostaglandin levels.[10] These data suggest that salicylate inhibits COX metabolism by a mechanism different from a direct inhibition of COX activity."
So, part of aspirin won't reach the circulation, deacetylation can occur before systemic distribution, and the other part is soon deacetylated. Salicylate level can remain elevated for hours.
That we will be dealing with ionized forms conflicts with lipophilicity.
Effect of Enteric Coating on Antiplatelet Activity of Low-Dose Aspirin in Healthy Volunteers
"Aspirin is deacetylated to
inactivesalicylate at a number of sites, including the gut; thus, its bioavailability is about 50%. Plain aspirin is absorbed from the stomach, where the low pH protects aspirin against deacetylation and maintains aspirin in a nonionized form which encourages absorption."The pKa of 2,6-DHBA is low enough that it can remain partially ionized even in the acidic pH of the stomach, which prevents intact absorption in an extreme scenario where gastric cancer cells were the desired target.
Therefore, I don't think that 2,6-DHBA being a 'strong' acid is a good reason to adopt it or a convincing explanation for the positive outcomes of use. Aspirin overdose can indeed result in acidosis, but would be an indirect effect.
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RE: Cancer
@Jennifer, I brought it up because a clinic that doesn't reject conventional methods altogether might be faced with less resistance by him. Another advantage is that it's located in national territory, not giving him the impression that he's seeking clandestine treatments abroad.
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RE: Aspirin metabolism: glycine and beyond
Not much glycine is lost with usual aspirin doses (30% or less of the aspirin weight).
The amount of sodium eliminated in pairing with salicylate ions should also be low. Approximations:
Aspirin
- 1 mmol per 180 mg (from 180 g/mol⇈)
- 5.5 mmol per 1000 mg
Sodium
- 5.5 mmol of sodium is 130 mg (from: 5.5 mmol × 23 mg/mmol)
Maximum direct sodium loss:
- 130 mg Na/g aspirin
It may seem negligible, but it depends on the amount consumed of each.
For a person ingesting an average amount of sodium (4 g), taking high doses of aspirin can induce the depletion of a considerable share of the sodium intake.
As for the alkalinization, it may enhance the activity of acyl-CoA synthetases (ACS), mentioned above as the limiting step, similar to the disinhibition effect on some glycolysis enzymes.
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RE: Cancer
@Jennifer, another approach that might suit:
Cancer Treatments | Cancer Center for Healing
↳ Low Dose ChemotherapyFrom them:
"Small portions of poultry or fish are also an option for patients who choose to adopt a “Mediterranean” style diet rather than a strictly plant-based (vegan) approach."
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RE: Aspirin metabolism: glycine and beyond
Yes, alkalinization tends to improve excretion of acids that ionize. The unionized forms are prone to leak from the kidney filtrate and lead to unwanted reabsorption.
What I find confusing in overdosing aspirin is that the most abundant metabolite appears to be salicylate, but it only protonates to salicylic acid when the pH is too low for the typical of urine, let alone for kidneys' tubules.
The pH role in the transport of active principles of drugs through agitated bulk liquid membrane
Therefore, the principle above don't seem to apply, unless the urine is extremely acidic, a shy fraction gets reabsorbed, and it becomes significant over time.
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RE: Cancer
@Jennifer, if your dad remains committed to conventional methods, perhaps he would be willing to consider this approach:
Immunotherapy in Cancer | Joseph Issels
"There are three general areas of prohost clinical management which are interwoven, and which overlap considerably:"
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"Correction of all known causal factors. This requires surgical elimination of foci of infection (notably head foci of dead teeth and nonfunctional diseased tonsils), immunization against pathogenic microbes and administration of appropriate flora, desensitization of local tissue pathologies caused by neural referral of disturbances from distant disease foci (Huneke), treatment of toxicoses and sensitivities caused by inherited latent phase cell wall deficient microbial forms (stemming from ancestral exposure to infections including syphilis and tuberculosis), which are passed on at birth and can persist for many generations (Enderlein, Spengler), replacement of pathogenic nutrition with a dietotherapy specifically designed to meet the special needs of cancer patients (Gerson, Hildenbrand), removal of environmental and psychological stressors as defined by Hans Selye, and the establishment of a more beneficial mind/body homeostasis according to the findings of psychoneuroimmunology."
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"Desensitization to causal factors. This is accomplished by systematic autogenous vaccination, application of microflora preparations and various specific vaccines."
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"Normalization of secondary damages to the host metabolism (impaired detoxification with subsequent suppression of natural defenses). Treatments include Gerson's dietotherapy, correction of the acid-base balance by treatment of the serum alkalosis and tissue acidosis paradox common in degenerative diseases, hyperthermia, fever therapy (Coley-Nauts), hyperbaric oxygen, ozone, ultraviolet blood irradiation, enzymes, glandulars, organ extracts, and neural therapy (Huneke)."
"Conventional anti-tumor treatments (surgery, radiation, chemotherapy) can be utilitarian and beneficial when modified to support the goals of whole-body comprehensive immunotherapy. In this context, they may be used concomitantly with vaccines, dietotherapy, and other host-protective medical measures. Dosages and duration of treatment with these drugs may be far less than is recommended in the randomized clinical trial protocols by which they achieved regulatory approval, but these modifications are justified by the outcomes of my patients, who achieve quite satisfactory tumor response without the typical side effects of hair loss, bone marrow suppression, and gut disturbances."
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