Archive for January 2007
Although salicylates have been used for centuries as treatment of inflammatory diseases, the mechanism of action of these drugs is still not clear. Aspirin (acetylsalicylic acid) and other nonsteroidal anti- inflammatory drugs (NSAID) inhibit prostaglandin biosynthesis, a property that appears to explain part of their anti-inflammatory activity. However, this mechanism does not appear to explain the anti- inflammatory properties of salicylic acid, which is a major metabolite of ASA in vivo. Results of prior studies in our laboratory have established that benzoic acid, the parent compound of the salicylate group of drugs, is decarboxylated and hydroxylated by the hydroxyl free radical (OH.) produced by stimulated granulocytes. These observations suggested that salicylates might be similarly metabolized by granulocytes. If so, the capacity of salicylates to rapidly react with OH. might relate directly to their known anti-inflammatory properties. Preliminary experiments established that salicylic acid and aspirin were decarboxylated by the hydroxyl free radical generated by the enzyme system xanthine-xanthine oxidase. We then studied the metabolism of salicylates by human granulocytes. Unstimulated granulocyte suspensions did not oxidize ASA or salicylic acid. However, suspensions stimulated by opsonized zymosan particles rapidly oxidized both substrates in pharmacological concentrations. The rate of oxidation of salicylic acid was 16-fold higher than benzoic acid, whereas the rate of oxidation of ASA was four-fold higher. The reaction was oxygen dependent and could be inhibited by known hydroxyl scavengers, particularly dimethylthiourea. The reaction could also be inhibited by superoxide dismutase and azide, indicating that O-2 and heme or an iron- dependent enzyme were required for the reaction. The reaction was not impaired by compounds known to react with the HOCL and the chloramines generated by stimulated PMN. Furthermore, salicylic acid in high concentrations did not impair the HMPS pathway, the production of O-2 or the production of H2O2 by granulocytes. These data provide evidence that salicylates are rapidly oxidized by the hydroxyl free radical produced by granulocytes and not O-2, H2O2, or HOCL. This capacity of salicylates to react rapidly and selectively react with OH. may directly relate to their anti-inflammatory properties. In addition, results of our experiments indicate that stimulated granulocytes acquire the capacity to metabolize these drugs. Therefore, several metabolites of salicylates may be produced at a site of inflammation, all of which may have altered biological activity compared with the parent compound. Oxidation of salicylates by stimulated granulocytes: evidence that these drugs act as free radical scavengers in biological systems
The difference in oxidation rate between salicylate and ASA might explain why there is a lower tolerance of salicylate than there is of pure ASA in a number of trials – perhaps it is the oxidised product that is more problematic?
The fact that salicylates are oxidised through xanthine oxidase is astonishing. Xanthine oxidase is a molybdenum dependent enzyme that produces bilirubin, bile, basically, that colours one’s poo brown. This might explain more fully the jaundice/yellow poo/hyper or hypo bilirubin problems in some salicylate intolerant people, especially after they go on the failsafe diet.
I’ve been wondering for a while about the anaemia link. Heme is a cofactor in the molybdoenzymes.
I had another “duh!” moment when I stumbled across this useful website about cerebral folate deficiency. According to the website:
Numerous drugs are known to inhibit the body’s ability to utilize folate including: 1) aspirin, 2) cholesterol lowering drugs, 3) oral birth control pills, 4) antacids, and 5) methotrexate when used for rheumatoid arthritis. Folinic Acid
According to the Linus Pauling Institute:
When taken in very large therapeutic dosages, for example in the treatment of severe arthritis, nosteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen may interfere with the metabolism of folate. Routine low dose use of NSAIDs has not been found to adversely affect folate status. Folic Acid
But what if they interact with your genes? One symptom I particularly associate with salicylates is a “trapped nerve” sensation in my neck. Folic acid is very important for proper nerve functioning and in myelin formation. I also get this symptom if I take too much B12 for too long.
The end results of folate or B12 deficiency is megaloblastic anaemia and high homocysteine levels. Both of these are associated closely with Parkinson’s, Alzheimer’s, and stroke. My paternal grandmother, the probable proband for my condition, developed Alzheimer’s before she died.
One of the weirder symptoms associated with folic acid deficiency is restless legs syndrome. It’s also a food chemical intolerance symptom. Aspirin use has long been associated with anaemia, though the cause is thought to be gastrointestinal bleeding. Aspirin use and the ingestion of toxic chemicals including benzene, are both associated with aplastic anaemia, a different type of anaemia.
There are studies on aspirin and folate balance:
To clarify the effect of aspirin on folate balance, we studied serum concentration, protein binding, and urinary excretion of endogenous folate. A healthy woman twice followed an 11-day protocol of constant diet, blood sampling twice daily, collection of all urine, and 650 mg of aspirin by mouth every 4 hours on the middle 3 days. As determined by equilibrium dialysis and Lactobacillus casei assay, aspirin induced a brisk, significant but reversible fall in total and bound serum folate and a small but insignificant rise in urinary folate excretion. Aspirin in vitro also displaced significant amounts of bound serum folate. Thus, aspirin in therapeutic doses can contribute to subnormal serum folate values, and if it increases urinary folate excretion even slightly, may impair folate balance. Aspirin and Folate Binding
Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase (AICAR transformylase, EC 220.127.116.11) and bovine liver dihydrofolate reductase (EC 18.104.22.168). In contrast, aspirin and the antipyretic-analgesic drugs acetaminophen and antipyrine were weak inhibitors of these enzymes. Structure-activity correlation suggests that an aromatic ring with a side chain containing a carboxylic acid is a requirement for competitive inhibition of the transformylase. The above-listed NSAIDs also inhibited the folate-coenzyme-mediated biosynthesis of serine from glycine and formate (i.e., the C1 index) by human blood mononuclear cells (BMCs) in experiments where the drug was added to a culture of BMCs. Acetaminophen had a weak inhibitory effect on the C1 index. Consistent with the results obtained in vitro is the observation that the C1 index of BMCs from rheumatoid-arthritis patients treated with drugs which possess little antifolate activity (e.g. acetaminophen) is higher than the C1 index of BMCs from rheumatoid-arthritis patients treated with NSAIDs possessing more potent antifolate activity (e.g. sulindac, sulphasalazine, naproxen and ibuprofen). The mean activity of the transformylase in BMCs taken from healthy humans was 1.98 nmol of product/h per 10(6) cells and the activity was positively correlated with BMC folate levels. These results are consistent with the hypothesis that (1) the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and (2) aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound. Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs
It seems to me that many of the mental symptoms of food chemical intolerance could be explained through a “blocking” effect of salicylates on folate. It explains why methylcobalamin helps my brain fog symptoms. It also explains why some autistics seem to respond to certain types of folate and to methylcobalamin. I had thought that autism was a more complicated condition, but it may simply be caused by genes combined with various food chemicals. For example a common MTHFR mutation or a DHFR mutation that makes autistics genetically more vulnerable.
I wrote a very long essay on cancer last year but took it down, and I really need to get it back online. In it I mentioned how a ketogenic diet has shown a lot of promise in treating cancer. Eades posted a couple of items on it last September.
The theory behind it is that cancer cells have defective mitochondria that make them 1) unable to burn fat and 2) forced to burn glucose through anaerobic fermentation, producing lactic acid as an end product.
This is copied directly from the marvellous New Scientist magazine:
It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their “immortality”. The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.
It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.
Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.
DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.
Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis’s experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).
Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don’t get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis.
Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become “immortal”, outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die.
“The results are intriguing because they point to a critical role that mitochondria play:
they impart a unique trait to cancer cells that can be exploited for cancer therapy,” says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester.
The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together. This means abnormal cells can be released and float to other parts of the body, where they seed new tumours.
DCA can cause pain, numbness and gait disturbances in some patients, but this may be a price worth paying if it turns out to be effective against all cancers. The next step is to run clinical trials of DCA in people with cancer. These may have to be funded by charities, universities and governments: pharmaceutical companies are unlikely to pay because they can’t make money on unpatented medicines. The pay-off is that if DCA does work, it will be easy to manufacture and dirt cheap.
Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. “The question is: which comes first?” he says. Cheap, safe drug kills most cancers
Acetic acid is basically vinegar, and one of the major ketones produced during low carbing, fasting, or weight loss. Wiki’s entry on Dichloroacetic acid:
Dichloroacetic acid (systematic name dichloroethanoic acid) is an analogue of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. It is prepared by the reduction of trichloroacetic acid.
The chemistry of dichloroacetic acid is closely related to halogenated organic acids. It is a member of the chloroacetic acids family.
Dichloroacetate stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenase kinase (Stacpoole PW. 1989; PMID 2554095). As such it decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. This property has been used to treat lactic acidosis in humans (Stacpoole et al, 1988; PMID 3337517).
In recent experiments at the University of Alberta, dichloroacetate has also been shown to regulate and restore normal metabolic functions in damaged mitochondria. This has proved particularly interesting in cancer cells, which do not self-terminate upon detecting abnormalities due to damaged metabolic functions. Tiny doses of dichloroacetate shrunk breast, brain, and lung cancers in both human and rat specimens. Dichloroacetic acid
Carolyn has reminded me that I haven’t linked to Plant Poisons and Rotten Stuff yet. This is my new self-help website for failsafers or people who suspect they may have food chemical intolerances to salicylates, amines, additives, MSG, sulphites, etc. I’ll also be writing some stuff about oxalates and polyphenols when I get around to it.
As you can see it isn’t finished, and barely even started, and a bit of a mess. There are like 3 pages on it at the moment. But I have a detailed copy of the elimination diet up there, and the advantage over the other copies you’ll find online is that it contains the food trials, and also that it’s easily printable!
It’s my birthday today. I’m thirty one. What a lovely subject for me to write about on my birthday. Though, relevant, in the sense that everyone appears to have decided thirty one is the age at which they can stop sending cards, presents, money, and emails… I was pretty depressed this morning.
I suppose if I start labelling myself with various official medical conditions, my friends who read this blog are going to start labelling me as “weird” (or, rather, “even weirder” – a label that one or two people will stick with forever, unless I set up a Freaky Friday experience for them to prove I am not making stuff up).
It’s taken me a while to figure this out. I have always been prone to depression. I was a very depressed teenager. Something is always wrong for me. There have been a few periods during my life when things have been quite good. I used to think of these periods as being my “not depressed” state. But they’re not. Looking back on them, I was totally high.
I can pinpoint a few of those times. When I went on holiday to the states for six weeks, I was off-the-wall high for the whole time. It actually made me do quite a few irrational things. When I was in the states, my cousin was killed in a road traffic accident. I knew that as soon as I returned to the UK I would be hit with the worst depression in the world. So my behaviour was avoidance, I put off returning, missed the funeral, even stayed a couple of weeks longer than I had arranged to. When I got back to the UK, I was hit full force by one of the worst depressions of my life.
The next time I was really high was when I first got together with my partner. Then we had to move to Sheffield because of work, and it totally took the wind out of my sails. When my boss at the time decided he’d make me redundant to save money on his failing business, I dropped through the floor (to save face I have to point out here that he was taking out a £70,000 wage, but he thought saving my £17.500 grand wage would turn things around).
The next time was when I started Atkins. I lost loads of weight, became really confident, felt sexy, bought lots of fashionable clothes. I was high for six months. Then we moved to France and I went even higher. I became a completely different person. Most of my life I’ve had a problem being able to talk to people. When I moved to France, I couldn’t stop gabbling. It’s like my symptoms switched over from the quiet, dreamy symptom set, to the loud, hyperactive symptom set. At the time I thought I was well. I thought I was healthy and normal at last. Then I got really sick, and a few weeks later we came back to the UK. I deflated over the course of about a month. That was the point when my eczema came back. It’s taken me until now to realise that I was not healthy and normal, I was High As A Kite. I was manic.
It used to be that people called bipolar disorder “manic depression” and only really, really ill people had it, and they were put on drugs and locked up in mental hospitals. Now bipolar disorder is recognised as being fairly common, and not nearly as extreme. There is another word for it too – cyclothymia. It basically means mini-bipolar disorder. The extremes aren’t as extreme, but there are still swings in both directions.
I was high before Christmas. We went for a short break to London. During the time we were there, I ate a lot of amines in the form of sashimi. I was in a state of what I can only articulate as “Wheeeeeeeeeeeeeee!” the whole time.
Two people very closely related to me describe themselves as being “a bit bipolar” or “a bit manic.” They have both been on antidepressants, something I would never do, having seen what terrible things SSRIs can do to some people. I guess it runs in the family. It’s really strange, but the problem with having this stuff running in the family, is that everyone regards it as normal and never labels it as a condition. I’ve always thought it was normal to have asthma, eczema, depression, ear ache, fibromyalgia… There was a point where I stopped labelling myself as having fibromyalgia because my symptoms were so normal to me that I just started to put it down to getting old. I was in my twenties.
Fortunately something else that runs in the family is my mother’s overpowering Sensible Streak. She has always been sensible. She’s always taught my sister and I to be sensible. I am the most sensible person on the planet. I don’t get irrational about things most of the time. If people try to jolly me along, I hate it, because I feel patronised. I know already! Duh! I always talk myself back from the brink without any help. I don’t think crazy things, I don’t do crazy things.
There are a group of synthetic antioxidants that range from E310-E312 called the gallates, including propyl gallate, octyl gallate and dodecyl gallate. They’re on the “nasty antioxidants” list. They’re based around gallic acid, also known as 3,4,5-trihydroxybenzoic acid – that’s right, they’re closely related to benzoates.
If you paint your skin with benzoates, you will get an instant rash. They’re thought to cause angioedema and urticaria by triggering not histamine but serotonin release.
Gallates reportedly cause the same effects as benzoates. These chemicals are notorious; they cause the full range of health problems like asthma, eczema, and the ADHD behaviour we’re familiar with in food chemical intolerant kids. Failsafe parents describe their children as having screaming fits when they are exposed to unlabelled antioxidants.
I had a small epiphany last night after reading something about green tea that had been posted on FailsafeNT. The chemical name of green tea extract had never struck me before.
Green tea extract is basically catechins, which make up as much as 25% of the dry weight of the tea. I once tried to lose weight on green tea extract, and I felt really run down, irritable and awful the whole time, and I kept recycling the same 2lbs on the scale.
The names of the catechins are: epicatechin, epigallocatechin, and EGCG (epigallocatechin gallate), the most abundant polyphenol of all. That’s right. Green tea is made of gallates. Green tea extract has been portrayed as a source of “wonderful” antioxidants. In actual fact green tea appears to be made up of the richest natural source of nasty antioxidants. Go look at the drawings of EGCG and gallic acid on wikipedia if you don’t believe me. EGCG is just a couple of gallic acid molecules tied together via another molecule, all arms protruding.
EGCG is even marketed as a “fountain of youth” for skin cells because it smoothes out wrinkles. Is this because, like other dodgy anti-wrinkle cosmetics, it’s causing angioedema? It’s marketed as an anti-inflammatory. Is this because it is acting like aspirin to block the all-important arachidonic acid pathway? Obviously if this is the case, it will cause asthmatic and pseudo-allergic reactions.
It’s really no wonder I had such horrible reactions to green tea extract, and in more recent trials, awful arthritis pains when I drink green tea.
Now I don’t care how many times EGCG helps me to recycle the antioxidant value of vitamin E, if it makes run around like a mental case until I fall over and burst into tears, I don’t want it in my body.
I haven’t been keeping this blog up to date. There’s so many things I need to blog about, but I just don’t have time! Hopefully this post will plug a few gaps for people.
Glycine is essential for the synthesis of nucleic acids, bile acids, proteins, peptides, purines, adenosine triphosphate (ATP), porphyrins, hemoglobin, glutathione, creatine, bile salts, one-carbon fragments, glucose, glycogen, and l-serine and other amino acids. Glucagon is a hormone that causes glycogen (stored in the liver) to convert to glucose which is needed by the body for energy. Glycine increases the release of glucose into the blood stream by stimulating the glucagon hormone. Glycine is an inhibitory neurotransmitter in the central nervous system, especially in the spinal cord. Glycine systems may be important in controlling epilepsy and other CNS disorders. Glycine also enhances the activity of neurotransmitters (chemical messengers) in the brain that are involved in memory and cognition. Glycine may be indicated to help alleviate the symptoms of spasticity. Glycine is an inhibitory amino acid with important functions centrally and peripherally. Molecular analogs and precursors can be used to augment these systems. The charged species have difficulty passing the blood-brain barrier and must be carried by transport pumps. Glycine helps convert many potentially harmful substances including toxic phenolic materials such as benzoic acid (sodium benzoate) into harmless forms. Vitamin Supplements
Glycine, along with Coenzyme A (derived from pantothenic acid) are required for salicylate detoxification through the amino acid conjugation pathway. This might be why I was dependent on pantothenic acid for a long time in order to feel normal, though it eventually threw my system so out of balance that it made me worse. However, glycine doesn’t seem to do much for me, which is why I’ve not bothered blogging about it. But trimethylglycine (betaine) does help a bit, especially with brain fog. As I am not protein deficient, I am producing enough glycine every day to meet my needs. For this reason I haven’t tried glycine on particularly bad reactions, or in really big doses, favouring TMG instead. I’ve only taken 500mg tablets of glycine in the past since I generally have a low tolerance of amino acid tablets. Glycine tablets tend to make me feel very depressed. It’s actually almost as though I’m having a glutamate reaction – probably because although glycine often antagonises glutamate in the brain, glycine also agonises glutamate on some receptors.
Vitamin B6 converts certain amino acids (glutamic acid, aspartic acid, glycine) to energy. This allows the body to process all dietary protein, even when the dietary protein is in excess of the body’s needs. Vitamin B6 also allows the body to synthesize certain amino acids. For example, if the diet is deficient or low in certain amino acids, such as glycine or serine, vitamin B6 enables the body to make them from sugar. Vitamin B6 is used also for the synthesis of certain hormones, such as adrenaline. enotes
B6 generally helps me a tiny bit when I am reacting, but it can make me feel worse if I take it every day.
Vitamin B-6 deficiency has been shown to increase urinary oxalate excretion. This represents the body’s inability to convert glyoxalate to glycine, which is necessary to synthesize glycine and serine. Springerboard
It’s interesting that a B6 deficiency causes a deficiency of glycine and an increase in oxalate production. I can see from this how prolonged, genuine B6 deficiency, OR a genotype/phenotype based low production of the enzymes involved, could cause hyperoxaluria in combination with a low tolerance for pharmaceutical doses of salicylate or benzoate.
The quantity of endogenous oxalate produced in these experiments must be related to the amount of oxalate precursors ingested and the degree of vitamin B6, deficiency produced. It appears from this study and that of Calhoun et al. in vitamin B6-deficient rats and the work of Archer et al. and Scowen et al. in cases of primary hyperoxaluria, that a considerable amount of urinary oxalate may be of endogenous origin and derived in great part from glycine. Oxalate has been shown to be formed from glycine via glyoxylic acid (10, 11) and inhibition of the system described by Cammarata and Cohen (12), i.e. glyoxylic acid plus glutamic acid, glycine plus a-ketoglutaric acid, could result in an accumulation of glyoxylic acid with increased oxalate formation. Endogenous Oxalate Synthesis and Glycine, Serine, Deoxypyridoxine Interrelationships in Vitamin B6-deficient Rats [pdf]
This is why glycine supplementation makes me very nervous, like everything else it can backfire and make things worse, and eventually it distorts something else. Unless you know exactly where the problem lies and what’s causing it, the odds are against you getting it right. This is why I don’t supplement regularly with anything anymore.
The body normally has plenty of glycine going spare – it is given to patients suffering from aspirin toxicity, but there is no evidence that someone who experiences side effects from the tiny quantities of salicylates in food (say, 1mg or so) would require supplementary doses of glycine. I think the human body would simply stop working if natural levels of glycine were so low they couldn’t soak up that little salicylate!