Chronotherapy: Taking the Treatment at the Right Time Has Major Impact on the Outcome

Dear Friends,

Chronotherapy (timing of drug delivery with the appropriate phase of the circadian rhythm to achieve optimal efficacy) is a subject I intended to write about since some years ago. But somehow I never found the time as I gave priority to other subjects. However, today I’ve got an alert on a new patent released on this subject and decided to start writing the post now as I think is good for people to be aware of this aspect, that could have important impact on treatment outcomes.

Essentially, the point that matters here is that the human body has various cycles is going through. Most are daily cycles, others may be weekly cycles, all of them extremely important for the effectiveness of our treatments, regardless if we speak about cancer treatments or any other illness. For example, humans have an internal clock that allows to adapt its physiology in anticipation of transitions between night and day. More specifically, this circadian clock induces oscillations of biological processes, such as sleep, locomotor activity, blood pressure, body temperature, and blood hormone levels.

This is basic knowledge related to the way how the human body works, yet not well connected with the way treatments (drugs, supplements) are given to humans.

Why that is so important?

Daily Cycles (Circadian rhythm)

The answer is relatively simple: The way out internal clock regulates, sleep, blood pressure, etc. is via some feedback loops that involve modulating the expression of various genes (Ref.). And that happens every day at specific hours. When that is broken, we can get various diseases such as metabolic disorders, etc. So, looking at daily rhythms during 24 hours, our body upregulates and downregulates a large amount of genes. But that growth and decline of the expressions changes at various hours during the day, that can be different for each gene. Now imagine that someone has health issues related to e.g. high cholesterol level, and that the gene related to the cholesterol production grows at nigh (which is the case), and that this person takes a (Statin) drug to lower that cholesterol production. But due to various reasons, he/she takes the Statin in the morning or at lunch time. However, each drug has a specific half-time (that indicates the time of action of a drug connected to the levels of the drug in the blood), which for most Statins is about 6h. You can now imagine that taking the statin in the morning while the mechanism targeted peaks at night is not a very good idea for the maximum effectiveness of a drug, since by the evening most of the drug is out of the patient’s blood.

Credit photo (Ref.)

Therefore, knowing

  1. what drug/supplement we are using and related half time of the drug on one hand, and
  2. what is the drug’s target and when that target peeks during the day,

can help us synchronize drug delivery with the appropriate phase of the circadian rhythm to achieve optimal efficacy, and may make the difference between effective treatment and non-effective treatments, whether is about oncology or any other illness we are treating.

Actually, we can “play” even more with this knowledge. For example, we can check when the right genes are most active to help the most cooping with chemo toxicity and reduce side effects of chemo (Ref.1, Ref.2). On this line, it has been shown that timing the Cisplatin treatment, by delivering in the evening instead of mornings, led to better outcomes with decreased renal toxicity and 2-4 times reduced treatment-related complications such as bleeding, infection (Ref.). Mathematical models suggested an important impact of the circadian control of DNA repair and apoptosis genes and proteins for irinotecan cytotoxicity. (Ref.) In a clinical study, it has been shown that gemcitabine-induced hematologic toxicity can be decreased by treating cancer patients at 9:00 ().

Here is a very good overview on the impact of circadian rhythm on the effectiveness and toxicity of various chemo therapies https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666849/  This is very relevant as it addresses many chemo.

The patent that triggered me today to write about this subject can be accessed here “NOVEL CHRONOTHERAPY BASED ON CIRCADIAN RHYTHMS” and it give’s a very good overview on various chemo-therapies and other therapies, their half-life, what they are targeting, and the time when those targets are at their maximum during the day.

From this patent we can even understand when is best to take Aspirin for the best results in term of prevention of heart attacks

If the above patent doesn’t contain the drugs of your interest here are a few links to databases that should help you get the knowledge you need in order to mach the drug with the right timing:

  1. Drug database including info on related half time and targets https://www.drugbank.ca
  2. Circadian Expression Profiles Data Base related to when that target peeks during the day http://circadb.hogeneschlab.org/

Here is Harmonizome, a BigData approach consolidating and facilitating the access to biomedical info, that could be of help http://amp.pharm.mssm.edu/Harmonizome/

And here is a good story on the path of an European oncologist in the quest of implementing Chemochronotheraphy: Chronotherapy: treating cancer at the right time

Circadian rhythms can be shifted/manipulated using two major tools: Light and Melatonin (Ref.)

Weekly cycles

While I find the daily cycles very important to be considered while trying to develop successful treatment strategies, it is the weekly cycles and their relevance in cancer treatments that got me excited many years ago.

Indeed, in 2009, a group of researchers from Australia published a paper (Ref.) suggesting three main important points:

  • in cancer patients the immune systems has a cycle of about 7 days
    • during which the immune systems is activated, reaches a peak, and then starts to be suppressed going towards a minimum
  • this cycle of the immune system can be correlated with CRP (C-reactive protein)
    • CRP is produced by the liver and by adipocytes in response to stress. The physiological function for CRP in the immune system is in attaching to and coating the surface of bacterial cell walls or to auto-antigens, to enhance the destruction or inhibition of bacterial cells or for the neutralization of auto-antigens. When inflammation occurs there is a rapid rise in CRP levels, usually proportional to the degree of immunological stimulation. (It can rise in about 6h with a max at about 48h.) When inflammation resolves the CRP rapidly falls (with a half-life of CRP is about 19 hours). Therefore, CRP can be utilized as a tool for monitoring immune activity in patients with a disease. (Ref.)
  • and can be used to build a treatment strategy
    • essentially, the authors are proposing to have immunotheraphy given at the minimum of CRP level which would be the point when the immune system will start being active, and giving chemotherapy around the maximum CRP level, to e.g. inhibit Tregs (which otherwise start inhibiting the immune system) and maximize immune reactions

The cycle has been detected in patients in a range of cancers: melanoma, ovarian, colorectal, brain, bladder, multiple myeloma, breast, oesophageal, lung, prostate and mesothelioma (Ref.).

The Australian researchers started a company focused on converting their findings into value for patients http://www.biotempus.com

On the other hand, there is also research suggesting that many other patients do not experience a cycle of CRP (Ref.). Here, the authors argue that the dynamic nature of the adaptive immune responses works two ways.

  • Firstly, there are diurnal fluctuations as discussed in the first part of this post, regulated by the circadian clock reflected in a rhythmic expression of genes that control cytokine secretion and cell function (.
  • Secondly, antigen dependent fluctuations occur during acute infections and the immune response is controlled by a system of positive and negative feedback mechanisms designed to limit the immune response when the enemies are resolved.

However, the authors further argued that in chronic diseases such as cancer, antigenic clearance does not occur and the persistent antigen exposure results in a constant state of immune activation, which in turn may not let the CRP fluctuate and may maintain a constant inflammatory state.

My opinion is that although different, both perspectives are helpful. There are various reactions in different patients as a function of the status of the patient and the tumor type and stage. And there may be some patients where a cycle can be identified and patients where no immune cycle can be found. Regardless on if there is a weekly cycle or not in a specific patient, what I think we can use from this research is the awareness related to the fact that high CRP relates to an overactive immune reaction and low CRP is equal to reduced activity, and based on this we may be able to design various treatment strategies, either using “chemo-like” or “immuno-focused” therapies as discussed above (Ref.). Although CRP measurements are relatively accessible and easy to perform with only a little blood from the finger, I can also imagine that some patients cannot have often access to CRP testing. Another way to have an idea about the status of CRP or of the immune activation is to measure body temperature every day. That should help understand what is the baseline temperature in a patient and when the immune system is active, in connection with body temperature rise.

Update April 19th: Funny enough, just one day after I published this article, one of the most prestigious magazine in the world, Nature, published an article exactly on this subject 🙂 “Medicine’s secret ingredient — it’s in the timing” https://www.nature.com/articles/d41586-018-04600-8

Other References:

Circadian Clock, Cancer, and Chemotherapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303322/

Cyclic haemopoiesis at 7- or 8-day intervals https://www.ncbi.nlm.nih.gov/pubmed/7528529?dopt=Abstract&holding=f1000,f1000m,isrctn We report a patient with severe anaemia and cyclic oscillations of reticulocyte and leucocyte counts, as well as serum iron (Fe), unsaturated iron-binding capacity (UIBC), ferritin, C-reactive protein (CRP) levels and temperature, at regular intervals of 7 or 8 d. After treatment with prednisolone, anaemia was corrected and the cyclic oscillations of these parameters ceased; whereas treatment with indomethacin, recombinant granulocyte-colony stimulating factor (G-CSF) and erythropoietin (Epo) were unsuccessful.

The circadian clock regulates cisplatin-induced toxicity and tumor regression in melanoma mouse and human models https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865687/ Our findings indicate that cisplatin chronopharmacology involves the circadian clock control of DNA repair as well as immune responses, and thus affects both cisplatin toxicity and tumor growth. This has important implications for chronochemotherapy in cancer patients, and also suggests that influencing the circadian clock (e.g., through bright light treatment) may be explored as a tool to improve patient outcomes.

Sancar lab finds final pieces to the circadian clock puzzle https://www.med.unc.edu/biochem/news/sancar-lab-circadian-clock-puzzle Sixteen years after scientists found the genes that control the circadian clock in all cells, the lab of UNC’s Aziz Sancar, MD, PhD, discovered the mechanisms responsible for keeping the clock in sync.

Circadian timing in cancer treatments https://www.ncbi.nlm.nih.gov/pubmed/20055686/ The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.

Cancer chronotherapeutics: experimental, theoretical, and clinical aspects. https://www.ncbi.nlm.nih.gov/pubmed/23604483  In the clinic, a large improvement in tolerability was shown in international randomized trials where cancer patients received the same sinusoidal chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed chronotherapy.

Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling. http://mct.aacrjournals.org/content/14/9/2154 The top-up of the multiple coordinated chronopharmacology pathways resulted in a four-fold difference in irinotecan-induced apoptosis according to drug timing. Irinotecan cytotoxicity was directly linked to clock gene BMAL1 expression: The least apoptosis resulted from drug exposure near BMAL1 mRNA nadir (P < 0.001), whereas clock silencing through siBMAL1 exposure ablated all the chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinotecan chronopharmacology. In vitro-in silico systems chronopharmacology is a new powerful methodology for identifying the main mechanisms at work in order to optimize circadian drug delivery. This finding suggested an important impact of the circadian control of DNA repair and apoptosis genes and proteins for irinotecan cytotoxicity.

Molecular Aspects of Circadian Pharmacology and Relevance for Cancer Chronotherapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666849/ The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceutics.

The liver circadian clock modulates biochemical and physiological responses to metformin https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657447/ Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Though it is a relatively safe and effective drug, clinical efficacy is variable and under certain circumstances it may contribute to life-threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic usage of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP-activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms impact the biological responses to metformin in a complex manner.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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23 thoughts on “Chronotherapy: Taking the Treatment at the Right Time Has Major Impact on the Outcome

  1. What a super interesting topic! Thanks for yet another brilliant article! It would be really useful if we can compile recommendations here in the comment fields, for when to take the typical re-purposed drugs to maximize their efficiency.

    1. I am glad you find it valuable, Carl. Thanks for your reaction. Indeed, mapping this info on to typical re-purposed drugs could help those who do not have the time to do own investigation with the “tools” provided above. What would be the list of the re-purposed drugs you think we should start with?

      1. This could be a starter:

        aspirin
        atorvastatin
        celebrex
        chlorquine
        cimitidin
        desloratadine
        dipyridamole
        disulfiram
        doxycycline
        hydroxychlorquine
        maraviroc
        mebendazole
        metformin
        naltrexone
        niclosamide
        propranolol
        simvastatin

        1. Here are the first two:

          Aspirin:
          – Main target Ptgs1: http://www.freepatentsonline.com/y2018/0071272.html
          – Max expression of Ptgs1 during the day: around 21 hours http://www.freepatentsonline.com/y2018/0071272.html
          – Half-life: 15 minutes; lengthens as the dose increases: doses of 300 to 650 mg have a half-life of 3.1 to 3.2 hours https://www.drugbank.ca/drugs/DB00945
          Therefore, taken before bed time it’s best.

          Atorvastatin:
          – Main target: HMGCR https://www.drugbank.ca/drugs/DB01076
          – Max expression: at night, after bed time http://www.freepatentsonline.com/y2018/0071272.html
          – Half-life: 3 hours https://www.drugbank.ca/drugs/DB00641
          Therefore taking it before bed-time is best.

          It takes a good amount of time to search each drug. I hope everyone will take a drug research it in the same way as above and share it here, so that it is much easier to perform the research and we can all benefit.

          1. Great! Thanks Daniel! Should max expression coincide with half-life, or peak-plasma (Cmax)? I suppose ideally with peak-plasma, but half-life is maybe a better indication since peak-plasma probably varies a lot between individuals.

            1. Indeed, perfect match would be difficult given the difference of absorption between individuals. However, it’s great to know that taking these drugs in the evening will likely lead to better results compared to taking them earlier in the day. It’s amazing to realize how large impact this could have and how little awareness is out there on this subject.

          2. For Simvastatin it definitely make sense with evening administration due to its short half-life, but since
            Atorvastatin’s half-life is +14h it is probably not as crucial.

            1. Thanks for letting me know Carl and sorry. I am doing my best – it’s a challenge keeping up with all the changes in plugins. Can you please check again if you can now add the post you tried before?

        2. Hi Carl,

          I also checked Propranolol:
          -Main target ADRB1 and ADRB2: https://www.cancertreatmentsresearch.com/propranolol-hexokinase-2-inhibiton-a-similar-anticancer-mechanism-as-that-of-3-bromopyruvate-3bp/
          – Expresion of ADRB1 is at 19:00 and that of ADRB2 is at 08:00 hours http://www.freepatentsonline.com/y2018/0071272.html
          – Half life: 4hours https://www.drugbank.ca/drugs/DB00571
          Therefore, it is best to take the drug at about 6:00am and/or 17:00 pm

          Kind regards,
          Daniel

        3. The following drugs have such long half-life that chronotherapy doesn’t seem applicable:
          Chloroquine: 1-2months
          Disulfiram: 7-14 days
          Hydroxychloroquine: 32 days

        4. Hi Daniel, do you agree with the following:

          MEBENDAZOLE:
          Description: inhibiting the synthesis of microtubules in parasitic worms
          Main target: TUBA1A
          Max expression (TUBA1A): Circadian time: 0 http://www.freepatentsonline.com/y2018/0071272.html
          Half-life: 2.5 – 5.5 hours https://www.drugbank.ca/drugs/DB00643
          Food interactions: Taken with our without food. Fatty food increases absorption
          Recommendation: Take Mebendazole at dinner time with fatty food
          Rational: Fatty food will increase absorption but slow digestion, hence why, given its half-life, administered at dinner time its half-life will coincide with the max expression of TUBA1A, 5-6 hours later.

    1. Hi Ieva. Nice to hear from you and very good question. I would think that Melatonin acts as a tiger to regulate the circadian rhythms. Here is an example of a study discussing the role of melatonin in the regulation of human circadian rhythms and sleep https://www.ncbi.nlm.nih.gov/pubmed/12622846
      This is important since as discussed in the post above (btw, I added a few more references since I published the post) treatments may be more effective at specific times, such as Cisplatin would be more effective and less toxic when given in the evening (assuming that the patient has a normal circadian rhythm that can be normalized by Melatonin). Off course, this is just one of the benefits of Melatonin next to all the others that I should discuss in a specific post dedicated to Melatonin.

        1. Careful with the blue light, while exposure might be useful during daytime, it’s harmful by night (if you must use light while sleeping, dim red is least harmful).

        2. Hi J, this is very interesting. Thanks!

          Just a summary for those too lazy to click on the link: 🙂

          – circulating nocturnal melatonin levels in the blood were 6-fold higher after exposing rats to blue light during the day (all day) and switched off at night
          – tumor (prostate cancer) latency-to-onset of growth and growth rates were markedly delayed
          – conclusion: “These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.”

          1. Yes, D, I found this one fairly surprising: adding a blue tinted window can have such a large effect on cancer? Most of the time you think that it will be necessary to go in with some extremely toxic chemotherapy to have any effect.

            I have been wondering about how chronotherapy might apply to something treatments such as 3-BP. The easy idea would be that during the night time the body’s metabolism must greatly slow down, and yet the metabolism of cancer might largely be unaffected. This is one of the big hallmarks of cancer: it does not respond to circadian or other cues. I would certainly wonder what might happen if one treated with 3-BP or other metabolic approaches when the cancer cells were still highly active and the rest of the cells were largely quiet. It is possible that the rest of the body’s cells might become more sensitive to 3-BP side-effects when they were in quiet mode, though it also seems quite possible that the cancer cells would become relatively more vulnerable. The big question might be related to whether there is a circadian cycle of the MCT-1 receptor expression.

            I would like to email one of the members of the forum. Are the email addresses of forum members somewhere on the public record? I thought I saw somwhere in the dashboard where with the email addresses.

            1. Hi J, indeed it would be interesting to know how MCTs are affected by the circadian rhythm. Everyone commenting needs to register and for that he/she should add the e-mail address. So I should have the address. Please check with the member and if he/she agrees with that I will send you the e-mail address.

              Kind regards,
              Daniel

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