Circadian Mismatch and Chronopharmacology

Part I: Circadian Mismatch

1. Artificial light at night suppresses melatonin (Lewy et al., 1980); induces “circadian mismatch.”

2. Circadian mismatch is associated with and/or predisposes to breast cancer (eg, He et al., 2014 and Yang et al., 2014).

3. In this epic study, human breast cancer xenografts were exposed to blood taken from healthy, pre-menopausal women during the day (melatonin-depleted), at night (high melatonin), or at night after light exposure (melatonin-depleted) (Blask et al., 2005). They showed that tumors exposed to melatonin-depleted blood exhibited higher proliferative activity than those exposed to melatonin-repleted blood. This has been deemed one of the most “ethical” studies to demonstrate a causal link between circadian mismatch and cancer.

4. And to make matters worse, circadian mismatch also reduces the efficacy of cancer drug therapy (Dauchy et al., 2014).  This study showed that, in a rodent model of breast cancer, exposure to light at night (circadian mismatch) enhanced tumor development and induced tamoxifen-resistance, and this was abolished by melatonin replacement.

melatonin

They also suggested a mechanism: tumors metabolize linoleate into the mitogen 13-HODE.  Melatonin suppresses linoleate uptake.

linoleate 13-HODE

 

 

 

 

Part II: Chronopharmacology

…more questions than answers

Taking uppers in the morning and downers at night is obvious.  Why isn’t this established for more drugs?

Disclaimer: fixing circadian mismatch should be prioritized, numero uno.  But some people still need drugs; if superior circadian dose timing allows for dose reductions and thus fewer side effects, I’m all for it.

Metformin used to be considered a dirty drug (ie, unknown or multiple targets), but the most likely target is AMPk, which inhibits the gluconeogenic enzyme PEPCK.  Doesn’t cause much hypoglycemia, but prevents hyperglycemia.  An interesting [preliminary] rodent study showed that metformin also induces circadian phase advance (Um et al., 2007)… 1) Does it matter what time of day metformin is administered? Seasonally? 2) Circadian mismatch is often caused by excess light at night = phase delay.  Is part of metformin’s efficacy due to countering this?

Another study showed that metformin increases the amplitude in circadian gene expression (Barnea et al., 2014).  Amplitude is blunted during circadian mismatch.  Is part of metformin’s efficacy due to countering this?

Thiazolidinediones are anti-hyperglycemic and anti-inflammatory; they cause weight gain but are otherwise effective.  Interestingly, one study showed that rosiglitazone directly targets Bmal1, a circadian transcription factor (Wang et al., 2008).  1) Does it matter what time of day rosiglitazone is administered?  2) Is part of rosi’s mechanism via Bmal1 activation?

Some pro-inflammatory cytokines exhibit a circadian peak in the early morning hours.  This is thought to worsen symptoms in some patients with rheumatoid arthritis in the morning, and one study showed that taking prednisolone (a synthetic glucocorticoid that suppresses inflammation) at 2 am, prior to the cytokine peak, was more effective than taking it at 7:30 am (Arvidson et al., 1997)… inconvenient, but could allow for dose-lowering.

Asthma follows the opposite rhythm: worse at night (in some patients).  Fortunately, some anti-asthmatic medications are already recommended to be dosed at night.

Blood pressure is supposed to dip at night, although this doesn’t happen in some hypertensive patients and this is thought to be of pathological importance.  Other hypertensives experience an exaggerated peak in blood pressure in the early morning.  Should their anti-hypertensive medication be dosed at night?  Researchers have already figured out that sustained-release meds taken at night solve these problems for some patients (eg, White et al., 1995 and 1997).

Bromocriptine, a dopamine agonist, reduces 24-hour blood glucose levels if taken immediately upon wakening… but people probably do this already (AM is the most common dose time for all drugs).

Urinary pH regulates renal excretion of some drugs; it’s lowest in the morning – this should be taken into account.

Some people are larks, others are owls.  Does this effect PK/PD or drug efficacy?  My guess is yes, at least for some drugs, because, for example,  it’s been shown that ACTH peaks almost 4 hours earlier in ‘morning people’ compared to ‘night people’ (6 am vs. 10am).

 

 

Chronopharmacology: new insights and therapeutic implications 

Circadian rhythms and medical diseases: does it matter when drugs are taken? 

^^^This paper has an awesome table showing dose-timing vs. efficacy on a great number of drugs.  They concluded: “Adequate evidence seems to support that at least ACE-inhibitors or ARBs, statins, corticosteroids (slow-release formulation) for arthritic patients, and ranitidine should preferably be administered in the evening. Morning dosing could be better for proton pump inhibitors, whereas time of administration is not crucial for asthma inhalation drugs.”

(needless to say, findings are mixed at this stage in the game)

 

Medication timing for the elderly: the impact of biorhythms on effectiveness

chronopharmacology dose timing

Statins work better when taken at night – possibly because this is when endogenous cholesterol synthesis peaks.  I’m not pro-statin, but if better dose-timing leads to lower dose requirements and cuts down on nasty side effects, then I’m all for it.  But really, I just mention TZDs and statins as examples of how circadian rhythms could impact drug dosing and/or metabolism, not reasons to take these drugs.

What about in people on low carb diets or intermittent fasting regimens, or night shift workers?  All. Bets. Are. Off.  This likely highly changes how drugs are metabolized, and they’d need to be re-tested in this context.  Oh well.

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  • Jack Kruse

    You know Bill the funny thing about breast cancer is that it is always linked to low Vitamin D levels. The key appears to be 30ng/dl.S.
    Hatse et al. “Vitamin D status in newly diagnosed breast cancer patients inversely correlates with tumor size and moderately correlates with outcome,” SABCS2011;AbstractP5-05-01.

    But here is the irony. Epithelial cancers are more tied to Vitamin D cousin, Vitamin A. Lung cancer and skin cancers show up with excessive vitamin A balance. This occurs when D3 is low. When this happens we also see a lack of cholesterol in tissues and cell membrane. Cholesterol depletion in cells forces them to switch to a nitrogen based transport for proteins. This forces eNOS to synthesize NO instead of sulfate. When sulfate levels drop this leads to wide cell damage from oxidation from RNS like perioxynitrite. This leads to kaotropes and chaotropes in the cell that cause protein mis-folding (see the Hoffmeister series for the details) When proteins mis fold cancer becomes a likely scenario. What people for get is we have many studies showing cancer rate rise when LDL cholesterol levels drop below 200. The key link is understanding that sulfate cholesterol makes sulfated D3 with the addition of UVB and IR light. There is only one double bond and one hydrogen difference between S-cholesterol and S D3 in the second ring of the sterol backbone. The double bond and extra hydrogen goes away due to the sun and not a chemical. So I think blaming breast CA on low D3 may actually miss the mark. I think it is a Vitamin A and cholesterol story and since no assays Vitamin A or sulfated cholesterol we miss the effect.
    When vitamin D3 levels fall, Vitamin A becomes unbalanced in tissues. When Vitamin A levels rise in tissues, inflammatory skin conditions and cancers in epithelium and neuro-ectodermal tissues are the usual result. The most interesting link is higher VItamin A levels in neuroepithelium also lowers sulfated cholesterol which actually makes Vitamin D 3 in the skin with UVB and IR light in these cells. Most of the eczema,acne, and dermatitis we see is tied to this imbalance. Eosinophilic esophagitis is also seen with this issue. You mentioned timing too in the blog……..UVB and IR light are at optimal frequencies 9-12 noon to make sulfate cholesterol and sulfate Vitamin D. This happens to be when testosterone and progesterone are at the peaks from the circadian cycle showing how the eNOS gets hit with the sun at the right time of the day naturally. Today we never see humans do that.

  • Jack Kruse

    One more thing…….we know low D3 increase glucose metabolism and AMPK signaling. This is tied to the circadian cycle seasonally and definitely impacts diabetics who take metformin. It is also why cycloset is used as an Early AM drug when it is used in T2D.

  • Jack Kruse

    They key to AMPK is to a transient calcium efflux in the cell. This slows ECT transport while being associated with a low D3 and higher A level in tissues.

  • Kindke

    Metformin activates AMPK through inhibition of AMP deaminase.

    I use metformin daily and really like it. if I take it in morning on an empty stomach it doesnt cause diarrhea, while it does when taken with food, Although if you take it alone I found it can cause hypoglycemia, will make you light headed and nauseous.

    I havent noticed much effect of metformin on phase advance however, if it does its very very short, 30mins-1hour. I did go to bed very *slightly* more early since taking it.

    Ill have to give bromo another go, but it tends to give quite severe insomina even when taken in the morning.

    Despite all the research and obvious health implications of shift work and working at night, this is not going to change. because money > health. There will always be people who are willing to work at night just to get a job. And there’s basically no going back on our 24hour society.

    • http://www.caloriesproper.com/ Bill Lagakos

      “I havent noticed much effect of metformin on phase advance however, if it does its very very short, 30mins-1hour. I did go to bed very *slightly* more early since taking it.”

      awesome… in this context, 30 minutes is huge!

    • Jack Kruse

      Kindke I appreciate what your implying and I think you are a very perceptive person. I want you to consider the following given what you have written about AMPK amplification and AMP deaminase in the liver: I said in the Tensegrity 7 blog that cholesterol sulfate plays a crucial role in the skin and liver by increasing both cholesterol and Vitamin D 3 sulfated forms. The skin part of the story is not important in this reply. But I will give you that context to further the point. Well it does the same thing in the skin from the light emitted from prokaryotes in the lumen. That proper specific frequencies of light from prokaryotes sets the stage to develop the sulfated version of D3 (quorum sensing) to interact with the VDR in the enterocytes and the GALT. This maintains the barrier in the gut and skin. Why? When D3 falls in enterocytes the tight junction break apart for one reason. When D3 falls, Vitamin A rises as a see saw would. Guess what vitamin A increases naturally? TRANSGLUTAMINASE…..the paleo bro science keeps telling you it’s grains that is the fundamental problem…….IT AIN’T. This is why Fasano’s latest research shows grains can’t be the only cause. This hurts the paleo business model so no one mentions it much but me. D3 forms a sulfate fortress that protect both the skin and gut. This is why leaky gut is always associated with skin issues like acne, roscea, and eczema. It is Vitamin A that is the real bad guy in skin and guts from a quantum perspective. The intestinal inflammation results and ruins the hydrogen bonding network in cell water. Iodine happens to be absorbed at the “blown up” tight jxns that Vitamin A destroys. So iodine transport is haywire too. This loss of iodine increases the space between H+ protons, and “results in low-grade fever” in the GALT’s immune cells. Especially macrophages that present antigens. This causes overactivation of immune system, allowing massive egress of gut pathogens easier access to the GALT where all hell breaks loose. What is the next protection Kindke? The liver.
      Ordinarily, the liver supplies cholesterol sulfate to the gall bladder, where it is mixed into bile acids, and subsequently released into the digestive system to assist in the digestion of fats. If a person consistently eats a high carb low fat diet, while avoiding the sun on their skin, the amount of cholesterol sulfate delivered to the digestive system from the liver is destroyed. This chain of events increase glucose metabolism and AMPK. More bugs get through the gut barrier. This fast forwards in this disease and the infections go wherever the barriers are weakest because cholesterol and DHA are missing in Cell Membranes EVERYWHERE as time goes by.

      The sulfate in the liver mixes with cholesterol comes from cysteine. Hence why I wrote Energy and Epigenetics 12 blog. Any insufficient bioavailability of cysteine will lead to a reduced production of cholesterol sulfate by the liver. THIS IS WHY Tylenol is deadly for someone on metformin. This depletes cysteine. Tylenol uses massive amounts of glutathione for clearance. This makes fat malabsorption the rule, not the exception for these patients. This is why they often begin to have micronutrient malnourished profiles on functional med testing. Moreover, they flock to carbs and avoid fat like the plague. This is where the paleo functional medicine type push people today. This induces the Crabtree effect in these people. It increases loss of cholesterol and DHA from cell membranes everywhere. D3 craters in response and glucose metabolism is selected for. ECT slows. All cells become chronically hypoxic and this DRIVES the liver to do something nasty.

      • Jack Kruse

        When this happens the liver converts glutamate to arginine and urea. Same thing happens with metformin to a degree. Depends upon the person’s redox potential who is taking it. I worry about metformin in many people. Glutamate is not something to mess around with in the liver. Why? It unleashes the calcium efflux from places it should be in “lock down”. Think malignant hyperthermia now. Glutamate is highly significant because it is produced mainly by the breakdown of amino acid proteins in the skeletal muscles. People forget cysteine is the RAREST AA in nature. BIG teaching point because once you are depleted of cysteine you go straight to muscle wasting to get it. They autodigest muscle in order to make enough glutamate to the liver to generate enough L-arginine to replace the role of sulfate in muscle glucose metabolism. I went into the nitrogen sulfate dance for O2 and glucose metbolism in Tensegrity 7.

        • Jack Kruse

          Now Kindke stay with me. A big point is coming. L-arginine is the major source of nitric oxide (NO). We need NO for glucose metabolism when sulfated cholesterol is MIA. Normally we use eNOS in summer to make sulfate, as I laid out in Tensegrity 7. eNOS switches its chemical function in cold weather seasons and uses nitrates to transport O2 and glucose in winter. Transport of glucose and O2 is dangerous in blood plasma…….so we have to change carriers as season change and eNOS is thermoplastic. I gave you that 3 yrs ago in CT-4 blog post. NO is a poor substitute for SO4 ?2 in summer……….but it works like a charm when its cold, your ketotic and hydrated. It becomes less dangrous to allow ROS and RNS in your plasma……….as it does in summer time but it can pinch hit for a short time if your redox is not trashed. Moreover, it can function in some of the missing roles. Sulfated cholesterol decreases in cell membranes when ECT slows, or we lose our electric charges, or we are hypoxic. Because sulfate delivers oxygen to myoglobin, it supplies cholesterol to the cell membrane under the quantum direction of DHA (Bill Lagakos alert), Sulfated cholesterol breaks down glucose specifically to protect the cell’s proteins from glycation and peroxidation damage. This protection is mandatory in a highly oxidative season like summer, because it is energy costly because it invokes ubiquination pathways and protein replacement. It costs the cell TONS of energy thermodynamically. NO helps reduce glycation, which helps DHA and O2 tissue delivery immensely. But here is the quantum key to understanding oxidaive damage: nitrogen can only be reduced from +2 to 0 whereas sulfur reduces from +6 to -2. That is a lot more electron protection. This is a way higher therapeutic index. This is why we use sulfur during summer and not nitrogen to transport O2 and glucose. Nitrogen is only safe when we are ketotic and inflammation is low and the zeta potential of the plasma is high.

          • Jack Kruse

            NO is a terminal oxidizing agent, so when we use nitrate pathways over the sulfate pathway from eNOS myoglobin becomes dysfunctional. Why? It is due to RNS and ROS oxidation and direct glycation damage from the altered glucose metabolism which is up regulated by low D3 levels and slow ECT flow, hypoxia, and increased AMPK regulation. Metformin can help here if the redox is not totally screwed. If it is it can make the situation worse and rhabdo is the result. It is a total fuck job to the mitochondria. So what happens to muscles when the mitochondria undergo a massive chronic forced REDOX shift (EE12 alert)? Muscles react as they can to survive this shift…….they engage in mitochondrial oxidation of glucose at their own risk hoping that the environmental shit storm they are in changes for the better soon. This is bail out maneuver to survive. This is why metformin gets it perceived benefit………but the therapeutic benefit depends upon a lot of assumptions. When some uses metformin it affects glutathione metabolism. De novo synthesis of glutathione, a folate-dependent pathway is interconnected with one-carbon metabolism is concomitantly depleted in response to metformin. This lowers cysteine and glutamate………remember glutathione is made of only 3 AA and two of the three are needed in this dance. So the longer you use metformin and engage in a Crabtree state the close you come to apoptosis and oncogenesis. It is a break…….but not a solution to a circadian mismatch.

          • Jack Kruse
          • Jack Kruse

            Life is about survival of the fittest. Lady evolution says its better to revert to anaerobic metabolism of glucose to decrease the risk of permanent damage to a cell. When you run out of options this is what you do. When you burn through all your mitochondria…….what happens next? ONCOGENESIS. This is why metformin gets its rep. Cancer in this scenario becomes an evolutionary survival mechanism where we shuffle the deck using our epigenomic toolbox using Barbara McClintocks jumping genes in the hopes of hitting a jackpot solution. So far our species does not have that answer, but we have only created a modern environment that favors a Crabtree metabolism for 150 yrs so. Given more time of this current shit storm technology has created (calcium efflux) it won’t be long before she figures it out a solution. Now…..recall that anaerobic metabolism of glucose results in a build-up of lactic acid, which, research from Dröge has shown further enhances the need for the liver to metabolize glutamate!!!! I have arrived at the point I wanted to make. Here we have another biochemical convection loop like the one I mentioned in Tensegrity 7. The lower your redox the faster metformin could kill you because it drains you of both cysteine and glutamate.

          • Dan Ordoins

            Jack is ketosis in the summer a mismatch then in our circadian rhythm? I typically run 100% ketosis – seafood based, occasional seasonal fruit but still levels me a fat burner through years of NK epi-paleo diet…. So if in ketosis during the summer and winter is there this NO and Nitrogen switch still happening? Looking to dial in optimal…. My redox is good and health markers seem outstanding so far.

          • http://www.caloriesproper.com/ Bill Lagakos

            “Jack is ketosis in the summer a mismatch then in our circadian rhythm?”

            I think it’s more that fruit & too many carbs in winter are a mismatch.
            Keto fare is available year-round.

          • Dan Ordoins

            Thanks. That makes sense.

          • Dr Josh Lamaro

            one must be careful that they have adequate stimuli for mitochondrial biogenesis/SO production at complex one if they stay keto in summer, i did it last summer without much exercise and winter hit me like a brick wall.

          • Jack Kruse

            normally yes……..but the world in which we live force a constant Crabtree effect due to the calcium efflux.