Chronopharmacology

"Pace, rhythm and timing is what it's about. The content's got to be great, but then it's got to be delivered. It's a tricky thing to do, and it takes a lot of work." - Ron White

Continuing with last newsletter’s theme of Nobel Prize winning ways, today I describe consequences of going along or going against the rhythms of our bodies, when designing therapies. In 2017, I was delighted to see that the Nobel Prize for Medicine / Physiology was awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for their description of the molecular mechanisms that control circadian rhythms. An area of great interest and work for me.

About twenty years ago, I enjoyed working with a client pulling together evidence to enhance their patent application; it described ‘uneven dosing formulations’ to improve therapies for many conditions and indications. It addressed the fluxuating efficacy and safety of fixed doses across the circadian rhythm/biological clock. Rather than changing dose timing, it proposed maintaining standard dosing intervals but instead adjusting the dosages for that time period. We came up with lots of ideas and supportive evidence for improvements. [And yes, the patent application was approved.]

[0002] This invention relates to novel dosage forms, drug delivery regimens, methods and compositions which optimize therapeutic effects of biologically useful Substances. The dosage forms, regimens, methods and pharmaceutical compositions of the present invention are adaptable to most biologically useful Substances, and will improve the effectiveness of Said Substances. Particularly Suitable Substances include, without limitation, anti-hypertensive agents, Osteoporotic agents, GERD agents, anti-viral agents, anti neoplastic agents, inhaled Steroids, anti-asthmatics, hormone replacement agents, anti-infectives, anti-diabetics, lipid lowering agents, thrombolytic agents, anticoagulant agents, fibrinolytic agents, nutritional agents, Vitamins, minerals, electrolytes, herbal agents and fatty acids.
[0003]. The present invention is particularly useful for adaptation to the Specific Schedules, cycles and needs of individuals, thereby frequently improving compliance with their therapy, reducing amounts required daily to less than conventionally utilized, and minimizing undesired effects commonly experienced. - US 2004/0062802 A1

Fig 1. A schematic overview of how chronobiology affects daily life and is an essential element of healthcare delivery. Zeitgebers maintain timing in the ‘master clock’ within the SCN, which in turn provides a reference point for the multiple ‘peripheral clocks’ throughout our organs. The peripheral clocks maintain normal body function, with the right processes being upregulated at the right time of day. Disruption of this delicate system can lead to detrimental clinical consequences. SCN, suprachiasmatic nucleus. D. Martin et al

Seems the field progressed since that time. Here are a few interesting findings.

NSAIDs

One of the largest, prolific category came from the NSAIDs (Non Steroidal Anti Inflammatory Drugs). Bone osteoclasts/osteoblasts cannot tear down and rebuild weight-bearing bone while it is bearing weight. It must do the remodeling of bone at times of rest. NSAIDs block the necessary inflammation required for this process of healing, occurring mostly at night. So stopping this with anti inflammatories is a big problem. [Also GI bleeding is worse after night NSAID dosing]. A mouse study of broken tibias clearly demonstrated that healing only occurred when NSAID dosing was in the awake phase and bones deteriorated when it was dosed at times of sleep.

Another NSAID indication is for pelvic pain. Cytokines are needed to remodel bone [circadian cycle] but also for follicular rupture in ovulation [a monthly cycle]. A study from Iraq of 39 women of fertile age suffering from minor back pain who received one of three NSAID drugs (diclofenac 100mg once daily, naproxen 500mg twice daily & etoricoxib 90mg once daily) evaluated effects on follicular maturation. Treatment was for 10 days starting at day ten of menstrual cycle. Compared to controls:

There was significant inhibition of ovulation in patients treated with diclofenac, naproxen & etoricoxib. Diclofenac was the highest inhibitor of ovulation compared to the other two drugs (naproxen & etoricoxib). A significant decrease in progesterone level in all three groups in compared to the control group was found. Functional cysts have been observed in one third of patients by the end of the treatment period with diclofenac, naproxen & etoricoxib due to unruptured follicles these disappeared at the next cycle. - Salman et al

These investigators even suggested we think about using NSAIDs as an emergency contraceptive. Hmmm…

Blood Pressure

Normally, blood pressure falls at night and increases upon awakening, in line with the body's circadian rhythm.

Recently researchers at UAB detailed the day-night rhythm of heart hormones, and how the disturbance of this rhythm could contribute to risk of high blood pressure and poor cardiovascular health in obese individuals. Obese individuals have a relative NP (Natriuretic Peptide) deficiency and disturbed BP rhythmicity. This misalignment of the NP-BP diurnal rhythm in the obese, may contribute to the disturbed diurnal BP pattern commonly found in the obese.

These studies give us a better understanding of NPs and of the reasoning behind the NP deficiency in obese individuals. We now have an FDA-approved medication (LCZ696) that improves circulating NP levels. This medication is considered a first-line treatment for heart failure and may be used to increase NP levels. -Pankaj Arora, M.D

‘Nondipping’ nocturnal blood pressure can be ameliorated with not just good timing of meds, but food too. A recent study of diabetic mice looked the effect of restricting eating times (not caloric intake) to 8 to 12 hours of 24, and found it normalized their night time BP back to the characteristic dip.

Just more evidence that we should always harmonize with our bodies if we want to be sure catch those ‘good vibrations.’

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REFERENCES

MAXIMIZING EFFECTIVENESS OF SUBSTANCES USED TO IMPROVE HEALTH AND WELL BEING https://patentimages.storage.googleapis.com/01/3d/ed/23597ae862da62/US20040062802A1.pdf

D. Martin et al. Rhythm and cues: role of chronobiology in perioperative medicine. British Journal of Anaesthesia Volume 121, Issue 2, August 2018,, https://www.bjanaesthesia.org/article/S0007-0912(18)30375-1/fulltext

NSAIDs Side Effects: When You Take NSAIDs is Critical https://regenexx.com/blog/nsaids-side-effects/

https://pharmaceutical-journal.com/article/news/nsaid-use-may-prevent-fertile-women-from-ovulating

Salman S, Sherif B & Al-Zohyri A. Effects of some non-steroidal anti-inflammatory drugs on ovulation in women with mild musculoskeletal pain. Annual European Congress of Rheumatology. 11 June 2015. http://dx.doi.org/10.1136/annrheumdis-2015-eular.1062

Vibhu Parcha et al, Chronobiology of Natriuretic Peptides and Blood Pressure in Lean and Obese Individuals, Journal of the American College of Cardiology (2021). DOI: 10.1016/j.jacc.2021.03.291

Tianfei Hou et al, Time-restricted feeding protects the blood pressure circadian rhythm in diabetic mice, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2015873118

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