Timing Nutriceuticals?

Abstract

Evidence on time-dependent effects of drugs and nutrition is succinctly reviewed in order to illustrate and advocate investigations of the timing of nutriceuticals. Emphasis is placed on the merits of coordinated, individually, inferentially, statistically examined sets of N-of-1 studies.

Fig. 1

Top: Three subjects consumed a single meal (2000 cal) per day, either in the morning (left) or in the evening (right). A cosine function with a period of 24 hours and a linear trend fitted concomitantly to the data were statistically significant 5 times (out of 6); P<0.05 for non-zero slope of trend 4 times out of 5 [6]. Results from more rigorous and extensive study on additional subjects over longer spans with control of mental and physical activities support, ceteris paribus, the finding of a relative body weight loss on breakfast. Bottom: Survival of mice dependent on housing conditions and timing of single daily meal. Young male BALB/c mice kept on LD12:12 lighting regimen with 4-hour span of daily food accessibility. Initial group sizes: A = 19, B = 20, C = 16, D = 16, E = 20; 1/C: housed 1 per cage; 4/C: housed 4 per cage. In this case, density per cage (allowing cuddling) represents an advantage rather than a disadvantage, a point of chronoecology. Experiment set up in Minnesota after reading of many deaths associated with lack of food, lack of clothing and cool weather among the palm trees of Benares on the Ganges. © Halberg.

Fig. 2

(A). Effect of single meal as breakfast- or dinner-only on the circadian cortisol rhythm. © Halberg. (B). Different displacement of circadian timing for different (hormonal and other) variables as a result of changing a single daily meal from breakfast to dinner. Whereas the circadian rhythm of circulating cortisol is only slightly affected by the timing of a single daily meal, considerable phase-shifts are observed for the case of growth hormone, insulin, and glucagon. © Halberg.

Fig. 3

(A). Consuming a single daily meal as breakfast-only (light bars) vs. dinner-only (dark bars) affects the direction and/or rate of body weight change. The single daily meal was 2,000 kcal given for 7-day spans. Breakfast (B); dinner (D). © Halberg. (B). Individual (vertical columns) and average (horizontal slashed bars) summarizing results in Fig. (3A). With one exception, there was a relative body weight loss on breakfast vs. dinner. Only one volunteer gained weight on breakfast vs. dinner. Overall, the difference in relative body weight loss on breakfast (B) vs. dinner (D) is statistically significant (P<0.05), whether a fixed 2,000 kcal meal or a single free-choice meal is consumed. Weight change (kg/wk) on D subtracted from that on B. In the study on one free-choice meal per day, subjects ate only breakfast for 3 weeks and only dinner for 3 weeks. In the study on one fixed 2,000 kcal meal per day, subjects ate only breakfast for one week and only dinner for one week. Note that mean relative weight loss is greater on fixed than on free-choice meal. © Halberg.

Fig. 4

Appetite (here defined as choice and amount of food) modifies the effect of meal timing on body weight. Relative body weight loss on breakfast-only (B) as compared to dinner-only (D) is less when meal is free-choice rather than fixed. Therefore, to minimize body weight loss when a single meal is consumed, it may be preferable not to fix the ration but to offer a choice. An overall summary of relative body weight loss on breakfast-only vs. dinner-only in the two studies described in Figs. (3A) and (3B) indicates that the decrease in relative body weight was more pronounced when a fixed 2,000-kcal meal was imposed than when volunteers could choose what they ate. © Halberg.

Fig. 5

Chronotherapy results on rats (top) [8, 9] and humans (bottom) [9, 10]. © Halberg.

Fig. 6

Substantial gains from chronotherapy. © Halberg [13, 14].

Fig. 7

Summary of effects on the MESOR (Midline Estimating Statistic Of Rhythm, M) of systolic (S) and diastolic (D) blood pressure (BP) assessed by self-surveillance by GC (F, 55y), who took coenzyme Q10 softgels (Q-Gel) supplementation (kindly provided by the Tishcon Corporation, Westbury, NY) at different times after awakening, namely upon awakening for one week, and at 3.5, 7, 10.5, 14 and 17.5 hours after awakening during consecutive weeks, while the 6 weeks of monitoring before the start of treatment served as reference. © Halberg.

Fig. 8

Circadian time-dependence of the effect of coenzyme Q10 upon the circadian amplitude (A) of systolic (S) and diastolic (D) blood pressure (BP) of GC. Note that treatment eliminated a pre-existing CHAT (Circadian Hyper-Amplitude-Tension). © Halberg [16, 17].

Fig. 9

(9A). Hyzaar induces CHAT in diastolic (D) blood pressure (BP) of one patient when given at some but not at other circadian stages. This figure is pertinent to large numbers of people worldwide, who are currently treated for high BP. They must realize that a popular drug, if prescribed without personalized surveillance, can harm by inducing a Vascular Variability Disorder (VVD), such as a circadian overswing or CHAT (Circadian Hyper-Amplitude-Tension). A change in the time when the drug is taken can make the same dose of the same drug in the same person beneficial rather than harmful or vice versa [21]. The drug can eliminate CHAT, a risk of stroke and other morbid events greater than a high BP, or induce it, depending on timing. Hyzaar was taken at one of 6 treatment times during waking, the schedule being changed monthly, with monitoring around the clock at 30-min intervals during the last week of each month. Differential effects on the MESOR (M) (top) and circadian amplitude (A) (bottom) of DBP. Differential effects of the same drug in the same dose in the same person occurring, all else being equal, as a function of the timing of the drug’s use along the scale of 24 hours, yet without an account for any infradian dynamics that should prompt repeated administrations at the time found optimal only or in the course of a second cycle of variations in treatment times. Continued surveillance is best best implemented to avoid harm. Study by Dr. Yoshihiko Watanabe. © Halberg. (9B). Hyzaar exacerbates a preexisting CHAT in the systolic (S) blood pressure (BP) of Figure 9a’s patient when given in the morning and eliminates this pre-existing VVD when given in the evening [21]. Study by Dr. Yoshihiko Watanabe. © Halberg. (9C). Without surveillance, we leave it up to chance and ignore whether we do harm at one time, shown in black (middle), while we can be beneficial at another time (right). © Halberg. (9D). If timing is not tested, insofar as vascular variability disorders (VVDs) are concerned (see Figs. 9A–C), the blind (care providers) lead the blind (care recipients) (bottom), showing the status quo. The painting at the bottom by Pieter Brueghel, “The Parable of the Blind Leading the Blind”, is reproduced by kind permission of the Fototeca della Soprintendenza of the BAS PSAE and of the Polo Museale of the City of Naples, in order to emphasize that CHAT is silent to both the caregiver acting on the basis of a conventionally interpreted (chronobiologically uninterpreted) 24-hour blood pressure as well as to the majority of providers treating on the basis of single measurements in their office. © Halberg.

Fig. 9

(9A). Hyzaar induces CHAT in diastolic (D) blood pressure (BP) of one patient when given at some but not at other circadian stages. This figure is pertinent to large numbers of people worldwide, who are currently treated for high BP. They must realize that a popular drug, if prescribed without personalized surveillance, can harm by inducing a Vascular Variability Disorder (VVD), such as a circadian overswing or CHAT (Circadian Hyper-Amplitude-Tension). A change in the time when the drug is taken can make the same dose of the same drug in the same person beneficial rather than harmful or vice versa [21]. The drug can eliminate CHAT, a risk of stroke and other morbid events greater than a high BP, or induce it, depending on timing. Hyzaar was taken at one of 6 treatment times during waking, the schedule being changed monthly, with monitoring around the clock at 30-min intervals during the last week of each month. Differential effects on the MESOR (M) (top) and circadian amplitude (A) (bottom) of DBP. Differential effects of the same drug in the same dose in the same person occurring, all else being equal, as a function of the timing of the drug’s use along the scale of 24 hours, yet without an account for any infradian dynamics that should prompt repeated administrations at the time found optimal only or in the course of a second cycle of variations in treatment times. Continued surveillance is best best implemented to avoid harm. Study by Dr. Yoshihiko Watanabe. © Halberg. (9B). Hyzaar exacerbates a preexisting CHAT in the systolic (S) blood pressure (BP) of Figure 9a’s patient when given in the morning and eliminates this pre-existing VVD when given in the evening [21]. Study by Dr. Yoshihiko Watanabe. © Halberg. (9C). Without surveillance, we leave it up to chance and ignore whether we do harm at one time, shown in black (middle), while we can be beneficial at another time (right). © Halberg. (9D). If timing is not tested, insofar as vascular variability disorders (VVDs) are concerned (see Figs. 9A–C), the blind (care providers) lead the blind (care recipients) (bottom), showing the status quo. The painting at the bottom by Pieter Brueghel, “The Parable of the Blind Leading the Blind”, is reproduced by kind permission of the Fototeca della Soprintendenza of the BAS PSAE and of the Polo Museale of the City of Naples, in order to emphasize that CHAT is silent to both the caregiver acting on the basis of a conventionally interpreted (chronobiologically uninterpreted) 24-hour blood pressure as well as to the majority of providers treating on the basis of single measurements in their office. © Halberg.

Fig. 9

(9A). Hyzaar induces CHAT in diastolic (D) blood pressure (BP) of one patient when given at some but not at other circadian stages. This figure is pertinent to large numbers of people worldwide, who are currently treated for high BP. They must realize that a popular drug, if prescribed without personalized surveillance, can harm by inducing a Vascular Variability Disorder (VVD), such as a circadian overswing or CHAT (Circadian Hyper-Amplitude-Tension). A change in the time when the drug is taken can make the same dose of the same drug in the same person beneficial rather than harmful or vice versa [21]. The drug can eliminate CHAT, a risk of stroke and other morbid events greater than a high BP, or induce it, depending on timing. Hyzaar was taken at one of 6 treatment times during waking, the schedule being changed monthly, with monitoring around the clock at 30-min intervals during the last week of each month. Differential effects on the MESOR (M) (top) and circadian amplitude (A) (bottom) of DBP. Differential effects of the same drug in the same dose in the same person occurring, all else being equal, as a function of the timing of the drug’s use along the scale of 24 hours, yet without an account for any infradian dynamics that should prompt repeated administrations at the time found optimal only or in the course of a second cycle of variations in treatment times. Continued surveillance is best best implemented to avoid harm. Study by Dr. Yoshihiko Watanabe. © Halberg. (9B). Hyzaar exacerbates a preexisting CHAT in the systolic (S) blood pressure (BP) of Figure 9a’s patient when given in the morning and eliminates this pre-existing VVD when given in the evening [21]. Study by Dr. Yoshihiko Watanabe. © Halberg. (9C). Without surveillance, we leave it up to chance and ignore whether we do harm at one time, shown in black (middle), while we can be beneficial at another time (right). © Halberg. (9D). If timing is not tested, insofar as vascular variability disorders (VVDs) are concerned (see Figs. 9A–C), the blind (care providers) lead the blind (care recipients) (bottom), showing the status quo. The painting at the bottom by Pieter Brueghel, “The Parable of the Blind Leading the Blind”, is reproduced by kind permission of the Fototeca della Soprintendenza of the BAS PSAE and of the Polo Museale of the City of Naples, in order to emphasize that CHAT is silent to both the caregiver acting on the basis of a conventionally interpreted (chronobiologically uninterpreted) 24-hour blood pressure as well as to the majority of providers treating on the basis of single measurements in their office. © Halberg.

Fig. 10

The Fig. (9) results followed-up on a study wherein immediately after the diagnosis of MESOR-hypertension, the time when a hypotensive drug was taken was systematically varied as an empirical approach to chronotherapy, for a first cycle of treatment (Rx) times at about 17-day intervals, with continued half-hourly monitoring of blood pressure (BP) and with more frequent Rx changes in a second confirmatory cycle of Rx time. This procedure is recommended for use at the time of diagnosis of each new case whenever the first Rx time, chosen to precede the early rise in any excessive BP MESOR (M, top) and/or amplitude (A, bottom), does not provide the desired response of all circadian parameters involved. Top: Successful Rx of MESOR-hypertension can be assessed by a self-starting cumulative sum (CUSUM) control chart. To optimize his hypotensive Rx, a just-diagnosed 24-year-old individual (TT) switched his Rx first every 17 days by 4 hours and then mostly at shorter intervals. Note statistically significant decrease in BP-M, evidenced by the breakout outside the decision interval of the negative CUSUM line. With continued Rx, the BP-MESOR leaves the decision interval, indicating a statistically significant decrease in overall BP. Note, however, that with Rx at noon, the slope changes direction. Bottom: Changing timing of Rx during consecutive spans shows risk of iatrogenic CHAT. It is important to ascertain that no vascular variability disorder (VVD, e.g., CHAT) is being induced by inappropriate timing of Rx. In TT, Rx in the evening was associated with an iatrogenic increase in the circadian BP-A. We must always check whether the risk of MESOR-hypertension may not have been traded for the even higher risk of stroke that CHAT represents. Iatrogenic CHAT, induced by Rx at 20:00 daily, is silent to measurement restricted to office visits. Some individuals may have traded benefit (lowering of the BP-MESOR) for something worse (CHAT). This danger applies to some hypertensives (who tend to have a large circadian BP-A) to whom Rx time is not specified by the care provider, as was the case for TT (or is specified for the morning for somebody who could benefit from Rx in the evening), as seen in Fig. (9). Rx time, if it is not fully acceptable, with a first specified timing, is best individualized, so that other-wise undetected harm is revealed and the condition is removed by optimized timing achieved with as-one-goes sequential analysis. © Halberg.

Scheme 1