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Chronotherapy is referred to and practiced in two different ways: (1) Chronotherapy (sleep phase) alters the sleep-wake rhythms of patients to treat sleep disorders such as insomnia, delayed sleep phase disorder, or depression.[1] (2) Chronotherapy (treatment scheduling), also called chronotherapeutics[2] or chronotherapeutic drug delivery,[3] refers to the coordination of therapeutic treatments with an individual's circadian or other rhythmic cycles to improve efficacy and reduce side effects[4]. These rhythms, regulated by the brain’s suprachiasmatic nucleus (SCN), influence physiological processes such as hormone secretion, metabolism, and immune function throughout the 24-hour day[5]. Originally developed for managing sleep and mood disorders, chronotherapy now spans a broad range of medical fields, including cancer treatment, cardiovascular care, psychiatry, and immunology[6][7]. By adjusting the timing of interventions—such as administering medications at specific times of day—clinicians aim to enhance therapeutic outcomes and minimize harm. Chronotherapy is distinct from chronobiology and chronopharmacology. While chronobiology is the broad study of biological rhythms, including circadian rhythms, chronopharmacology narrows this scope to the study of how a drug's effects vary with biological timing. Chronotherapy applies this knowledge clinically, including timing of treatment to improve outcomes and reduce side effect[8]. Recent studies have shown that many diseases follow circadian patterns in symptoms and treatment responses. As a result, interest in chronotherapeutic strategies has grown, supported by advances in circadian research, personalized medicine, and wearable health technology[9][10].

History and Development

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The concept of chronotherapy emerged from decades of foundational research in circadian biology, clinical pharmacology, and translational medicine. The evolution of chronotherapy reflects a growing understanding of how biological timing can influence health and disease, shaping both experimental models and real-world treatment strategies.

Early Chronobiology Research

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Chronotherapy is deeply rooted in the early work of pioneers in circadian biology such as Franz Halberg and Colin Pittendrigh. Halberg introduced the term “circadian” and was instrumental in identifying physiological rhythms in humans and animals, while Pittendrigh’s work helped define the concept of the endogenous biological clock and its entrainment by environmental cues[11]. These early findings laid the groundwork for understanding how timing influences biological systems, an essential premise for chronotherapy[11].

Initial Clinical Observations

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In the 1980s and early 1990s, clinical researchers began observing time-of-day variations in drug pharmacokinetics and therapeutic responses. For example, drugs were found to be absorbed, distributed, and eliminated differently depending on the timing of administration[12]. These discoveries led to the development of chronopharmacology, a field focused on the timing-dependent effects of medications. Reinberg’s work in the early 1990s highlighted how circadian patterns could inform the optimization of treatment schedules for various conditions, including asthma, cardiovascular disease, and arthritis[13].

Growth in the 1980s-2000s

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The application of circadian principles to cancer treatment marked a major turning point for chronotherapy. French oncologist Francis Lévi pioneered cancer chronotherapy, demonstrating that chemotherapy administered in sync with circadian rhythms could significantly improve efficacy and reduce side effects[14][15]. By timing drug delivery to avoid periods of maximum toxicity to healthy cells, Lévi’s work showed that personalized treatment schedules could enhance outcomes in colorectal and other cancers. This period also saw the development of infusion pumps designed to deliver medication at programmed times, further advancing the field.

Modern Chronotherapy

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Chronotherapy has continued to evolve beyond oncology, influencing research in neurology, psychiatry, and respiratory medicine. Recent studies have explored how rhythmic treatment schedules may slow tumor growth in gliomas[16], improve outcomes in asthma and Chronic obstructive pulmonary disease (COPD), and even enhance mental health therapies. As understanding of circadian biology expands, more clinical trials are integrating time-of-day considerations into treatment protocols[17].

Technological Contributions

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Recent technological advances have accelerated the clinical potential of chronotherapy. Wearable sensors, smart infusion devices, and bioelectronic systems can now track circadian biomarkers and deliver time-sensitive therapies with precision[18]. In the context of hematological malignancies, digital health tools and machine learning algorithms are being explored to tailor treatment timing to individual patients' circadian profiles[19]. These innovations are helping transform chronotherapy into a key component of personalized medicine.

Principles of Chronotherapy

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Chronotherapy is grounded in the understanding that biological functions in humans follow a roughly 24-hour cycle, known as the circadian rhythm. These internal rhythms influence numerous physiological processes, including sleep-wake cycles, hormone secretion, immune response, metabolism, and cell proliferation[4].

Timing of Interventions

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One of the key principles of chronotherapy is that the effectiveness and side effects of treatments can vary depending on the time of day they are administered. This is due to circadian variation in drug absorption, metabolism, and target sensitivity. For instance, cancer chronotherapy adjusts chemotherapy timing to match tumor cell cycles and reduce toxicity[20]. Similarly, light-controlled interventions are being explored to precisely regulate gene expression and circadian phases using optogenetics and photopharmacology[21].

Mechanisms of Circadian Rhythms in Medicine

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Circadian rhythms are regulated by an internal timekeeping system that orchestrates daily physiological and behavioral cycles. Understanding the biological mechanisms underlying these rhythms is essential for developing effective chronotherapeutic strategies in medicine.

Central and Peripheral Clocks

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At the core of the circadian system is the suprachiasmatic nucleus (SCN), a small region in the hypothalamus that acts as the body’s master clock. The SCN receives direct input from light-sensitive retinal ganglion cells and synchronizes peripheral clocks located in nearly all tissues and organs. These peripheral oscillators maintain local rhythmicity but rely on signals from the SCN to remain coordinated with the external environment[11].

Molecular Clock Genes

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The circadian system operates through a transcription-translation feedback loop (TTFL) involving core clock genes. Key components include CLOCK and BMAL1, which form a heterodimer that activates the transcription of PER and CRY genes. The PER and CRY proteins accumulate in the cytoplasm and eventually inhibit their own transcription by interacting with CLOCK-BMAL1, completing a roughly 24-hour cycle[11].

Gene Expression Rhythms

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These molecular oscillations lead to daily rhythms in gene expression across thousands of genes involved in metabolism, inflammation, DNA repair, and cell cycle control. The timing of gene activity is tissue-specific, and disruptions in these rhythms can affect susceptibility to disease and responsiveness to treatment. Understanding these temporal patterns has helped identify optimal windows for drug administration in chronotherapy[4].

Chronotherapy and Implications

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Disruptions in circadian rhythms are increasingly recognized as contributing factors in obesity, diabetes, and other chronic conditions. Chronotherapy seeks to mitigate these effects by aligning treatment with biological rhythms. For example, the timing of food intake and insulin therapy has been shown to affect glucose metabolism, and aligning these with circadian cycles may improve outcomes in metabolic disorders[22]. Similarly, timing antihypertensives or psychiatric medications to match hormonal rhythms may enhance their effectiveness while reducing side effects[17].

Chronopharmacology: Drug Timing and Efficacy

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Chronopharmacology is the study of how the effects and pharmacokinetics of medications vary according to the time of day they are administered. This field plays a key role in chronotherapy, as aligning drug delivery with circadian rhythms can significantly improve therapeutic efficacy and minimize adverse effects[23].

Chronokinetics and Chronodynamics

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Chronokinetics refers to circadian variations in the absorption, distribution, metabolism, and excretion (ADME) of drugs, while chronodynamics refers to variations in the pharmacological effect of a drug depending on biological timing[24]. Numerous physiological processes—including gastric pH, hepatic enzyme activity, renal clearance, and blood flow—follow circadian patterns, influencing how the body processes medications throughout the day[25][26].

For example, bronchodilators used in asthma treatment have shown variable effectiveness depending on administration time, due to circadian fluctuations in lung function and receptor sensitivity[27]. Similarly, antihypertensive medications such as ACE inhibitors can produce different blood pressure-lowering effects when taken in the evening versus the morning, with evening dosing often leading to better overnight control and cardiovascular outcomes[28][29].

Chronokinetic variability has also been demonstrated in psychiatric medications, antibiotics, and cancer therapeutics, highlighting the broad relevance of circadian principles across clinical fields[30][31].

Limitations and Challenges

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Chronopharmacology faces several methodological and practical barriers. Biological rhythms are often overlooked in clinical pharmacokinetic studies, introducing variability in results and limiting reproducibility[32]. Furthermore, individual differences in circadian phase (e.g., due to chronotype, age, or light exposure) complicate efforts to generalize timing recommendations[32].

Additional challenges include logistical issues in administering medication at specific times, limited awareness among clinicians, and the need for more precise biomarkers to assess circadian phase in patients. As digital health technologies and wearable circadian trackers advance, some of these barriers may be overcome, enabling wider adoption of chronopharmacologically-informed care.

Chronotherapeutics

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There are numerous forms of chronotherapy, including medicine, light, and food [33] that can aid in the treatment or prevention of various diseases.

Chronotherapeutics Targeting the Sleep-Wake Cycle

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Chronotherapy can target the sleep/wake cycle to treat circadian rhythm sleep disorder, defined as alterations in the sleep-wake rhythm due to the internal clock's inability to synchronize with the external environment[34]. Circadian misalignments can include alterations in the phase of the rhythm, such as delayed sleep phase disorder (DSPD), characterized by a delayed 3-6 hours sleep onset and offset relative to the socially acceptable sleep-wake schedule[35]; advanced sleep phase disorder (ASPD)[35], characterized by early sleep-wake time; irregular sleep-wake rhythm disorder (ISWRD); non-24-hour sleep-wake disorder[35]; jet lag; and shift work[36].

Chronic misalignment of the clocks has been associated with metabolic syndrome, cardiovascular disease[37], mood disorders, reduced immune function[38][39], obesity, and diabetes. Poor sleep quality has been identified as risk factors for cognitive decline, neurodegenerative disease, and depression[40][41]. "Social jetlag”—a mismatch between biological time and social obligations—can lead to sleep deprivation and long-term health risks[38]. Sleep is also closely linked to immune function[42] and cancer[43]. Interventions such as bright light therapy and melatonin supplementation are used to help realign circadian timing[44]. It has been reported that chronotherapy in depressed patients follows the two-process model of sleep regulation, resulting in profound and rapid amelioration of depressed mood in 60% of the patients via increasing the homeostatic sleep pressure and a phase advance of sleep[45].

Light Chronotherapy

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Light chronotherapy, sometimes referred to as light therapy, is also used to cause a phase delay or advance in sleep onset and is often used in the treatment of psychiatric conditions. Light chronotherapy often involved enhanced light exposure at wake, with little to no short-wavelength light exposure just before sleep[46]. Light therapy is often used to treat circadian rhythm disorders[47][48] and seasonal affective disorder (SAD)[47][49]. Further, light therapy can be used to realign the circadian clock to reset melatonin and cortisol imbalances, leading to reduced CVD risk[50]. Further, mice studies have shown an improvement of cardiac function with Light-emitting diode therapy with heart failure, upregulating calcium transients and ATP synthesis in cardiomyocytes[51]. However, side effects of light therapy include headache and nausea, and patients must be monitored for emergence for hypomanic or manic activity[52].

Light chronotherapy is used to treat DSPD by progressively advancing the patient's sleep time by 2 hours every day until the desired sleep time is achieved. Timed broad-spectrum bright light of 2,000-10,000 lux exposure in the early morning (6:00-8:00 a.m.) for about 1-3 hours is commonly used for DSPD to advance the phase of circadian rhythms[53]. However, the registry and survey of circadian rhythm sleep-wake disorder patients have shown that light treatment was not successful in a substantial number of patients[54].

Phase-delay chronotherapy

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This treatment regimen is used for treating DSPD, recommending that patients delay their sleep time by 3 hours each night until their sleep is shifted to a desired sleep window. This treatment has been associated with alarming side effects: 11% subsequently received a clinical diagnosis of non-24-hour sleep-wake disorder[55].

Chronobiotic

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Drugs that influence, directly or indirectly, the phase and/or period of a circadian clock are known as chronobiotics. An ideal chronobiotic drug should therapeutically recover desynchronized circadian rhythms in the short or long term, stabilize the body rhythms, and synchronize the internal rhythms with the environment with few side effects[56].

Melatonin (MLT), secreted rhythmically by the pineal gland, is one of the prototypic chronobiotics that coordinates circadian rhythmicity via its response to signals from the SCN in response to environmental photoperiod. It meets most of the criteria for ideal chronobiotics [57]. Notably, the presence of MLT receptors in the SCN indicates that exogenous MLT can affect the SCN. In rodents, daily administration of MLT through injection, water supplies, or subcutaneous infusion entrains free-running locomotor activity rhythms at the end of the light period. In humans, the use of MLT has been reported to treat circadian rhythm sleep disorders such as delayed-phase sleep syndrome, advanced-phase sleep syndrome, etc. Notably, there is evidence that melatonin has a role in the treatment of some primary sleep disorders, namely primary insomnia, Delayed Sleep Phase Syndrome (DSPS), non-24 hour sleep-wake disorder and in people who are blind[58].

Due to the many clinical limitations and poor compliance with light therapy, exogenous melatonin (0.3–3 mg) administered 1.5–6 h before bedtime, offer an accessible treatment venue for DSPS[59]. Afternoon or evening administration of melatonin shifts circadian rhythms and the nadir of core body temperature to an earlier time[60][61][62] . However, the optimal time and dosing of melatonin administration have not yet been established. Some studies have used 5 mg, but another employed 0.3–3 mg [63].

Chrononutrition

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Studies have the effects of restricted dietary timelines on sleep, performance, and alertness[64].  Examples of chrononutrition application include intermittent fasting, meal latency, and meal skipping[65]. In 2009, researchers showed mice on a high-fat diet during the day gained much more weight than those who received the same diet at nighttime[66].

Clinical findings suggest time restricted eating may promote metabolic benefits including weight loss, have shown little to no effects on glucose and lipid profiles[67]. Many studies have investigated chrononutrition within metabolic diseases including obesity, type 2 diabetes, and non-alcoholic fatty liver disease, with mixed results on weight and fat loss[67]. Food intake schedules were also analyzed for their effects on CVD risk. In the NutriNet-Santé study, results showed eating meals later in the day was associated with greater CVD, and that earlier dinner, rather than eliminating breakfast, may aid in CVD risk reduction[68].

However, the exact mechanisms by which the nutrients are processed within the body differently at alternate points within the day is still unknown[66]. Further, a 2019 cross-sectional study on the effects of intermittent fasting during the month of Ramadan showed that the fasting could lead to severe hypoglycemia[69]. Further, research presented at an American Heart Association conference has suggested that intermittent fasting (8-hour feed restriction) can lead to a 91% increased risk of dying from a cardiovascular disease[70]. Furthermore, meal skipping has been shown to need to an increase in energy and caloric intake at the subsequent meal, reducing daily energy intake, but also diet quality[71].

Chronotherapeutic Drugs within Disease Management

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The body can metabolize or react differently to stimuli based on its oscillatory daily output, indicating some treatments may be better in the morning, while others during the nighttime. In 2021, less than 1% of the United States’ legalized medications have a preferred administration time listed[72], even though 56 of the top 100 best selling drugs target.

Individuals vary in their natural circadian timing, commonly described by chronotypes. Some people are naturally inclined to be more alert in the morning (“morning types”), while others peak in the evening (“evening types”)[73]. The development of Chronotherapy continues to bring more precision, allowing physicians and researchers to develop patient-specific pharmacological and nonpharmacological treatments carefully designed to maximize efficacy to one's chronotype[74].

Cardiovascular Disease (CVD)

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Studies have shown differences in patient complications after aortic valve replacement when performed in the morning versus afternoon. Those treated in the afternoon had lower major adverse cardiac events compared to those operated on in the morning. This was backed by findings indicating circadian clock controlled element Rev-Erbɑ was highest in the morning, and antagonizing this element showed cardioprotective effects[75].

The Hygia Chronotherapy Trial assessed the effects of patients taking daily hypertension medication at bedtime or at wake. The study found bedtime administration had lower hazard ratios and chance of CVD events[76]. Further, verapamil, a calcium channel blocker used to treat hypertension, was the first chrono-modified hypertensive drug with controlled onset and extended-release properties for nighttime administration. This system permitted delivery 4-5 hours after administration, with greatest antihypertensive effects in the morning, which is when blood pressure is shown to peak throughout the day[77][78]. Similarly, randomized trials in hypertension have shown that nighttime administration of blood pressure medications results in better 24-hour blood pressure control and reduced cardiovascular risk compared to morning dosing[28]. See Future Directions

However, the Hygia Chronotherapy trial has been scrutinized for its methods and results, with large discrepancies shown in other studies such as the 2005 Dublin outcome study[79]. Due to the questions raised, the European Heart Journal did investigate the trial and reported no ethical or factual concerns, however investigation by the European Society of Cardiology reported they could not verify source data in the Hygia trial. Because of the uncertainties, in 2022, the International Society of Hypertension reported they did not endorse bedtime dosing medication[80].

Clinical evidence has shown that the timing of administering antihypertensive medications to a patient's endogenous circadian rhythm influences cardiovascular outcomes. [81]

Across various pharmaceutical specialities, scientists are continuing to discover the importance of patient specific chronotherapeutic practices, with many researchers finding various efficacy results dependent upon whether a chronotherapy is administered during the morning or evening.

Rheumatoid Arthritis (RA)

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Rheumatoid Arthritis (RA) is characterized by a symptom known as morning stiffness, with an increase in swelling and pain in the afflicted joints occurring early in the morning or after a long sedentary period[82]. This is believed to be due to an imbalance between melatonin and cortisol levels, with insufficient cortisol elevation to combat pro-inflammatory nighttime melatonin secretion[83].  The RA drug prednisone, a corticosteroid, has been shown to have a greater impact when taken at bedtime compared to at wake, consistent with a prevention of the pro-inflammatory cascade, rather than administration at the peak, when it may become more difficult to dampen. Further, newly modified controlled release prednisone with drug release at approximately 02:00AM has been shown to be further optimized for symptom reduction[84].

Further, methotrexate (MTX), a common disease modifying rheumatoid arthritis drug (DMARD) has been shown to also benefit from chronotherapeutic administration. Studies have shown that administration at bedtime daily reduced RA symptoms compared to the standard three times a week administration of MTX[85].

While chronotherapy in RA is considered widely accepted, the impact on patient outcomes is still lesser than new drugs and newer treat-to-target strategies. Therefore, it may be considered more-so as a complimentary strategy[84].

Oncology

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Chronotherapy in cancer attempts to optimize the administration of anti-cancer drugs and minimize toxicity based on one’s daily rhythms. Both chronotherapeutic delivery of radiation and drug chemotherapy has been shown to minimize toxicity and reduced side effects including nausea and vomiting[86].

A well-known documented case of cancer chronotherapy was performed on a 21-year old who present with an ovarian endodermal sinus tumor in 1973[87]. In sequential months, this patient was given medications at different times throughout the day, to determine which would be optimal for the patient autorhythmometry. Based on the data, they determined administration at 4:00 a.m. to be optimal. However, the assessment of patient vigor and mood was largely subjective and self-rated, so it may not be fully accurate[87].

Further, in treatments such as glioblastoma (GBM), a 2021 study suggested a potential for morning administration of temozolomide (TMZ) to extend patient survival by over 3 months[88][89]. However, a 2022 study showed that there was no difference in patient survival between morning and evening administration[88][90].

Clinical research also supports the time-dependent nature of drug efficacy in several therapeutic areas. Studies in cancer chronotherapy have demonstrated that delivering chemotherapy agents like oxaliplatin, 5-fluorouracil, or varying light hues at specific circadian phases can reduce toxicity, enhance anti-tumor activity, and expedite recovery [14].

Lastly, Bright light therapy, a non-pharmacologic intervention consisting of exposure to bright light hues has shown to reduce fatigue and improve quality of life in breast cancer survivors when tailored to individual circadian patterns. [91] However, there is still further research necessary to better understand the individualized efficacy regarding specific light hues and their effects on breast cancer rehabilitation. [92] From a pharmacologic standpoint, researchers have also found that the efficacy of drug administration can be dependent on a patient's chronotype.[93] Additional oncology research also highlights chronotherapy as a means to improve sleep quality and minimize fatigue for breast cancer survivors. [94]

Despite recent advancements, several studies have shown inconclusive results on radiation and drug timing, therefore more work is needed to examine the effects of chronotherapy within cancer treatment, and whether the tumor type and grade specificity at which it may be applicable. See Future Directions

Immunizations

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Vaccine efficacy, specifically its antibody production and efficacy, has proven shown to fluctuate based on time of administration[95][96], likely due to rhythms in immune fluctuations[95]. Termed “chronovaccination,” the COVID-19 pandemic sponsored new interest into how the vaccine efficacy may change throughout the day. Morning vaccinations for COVID-19, influenzas, hepatitis B, and hepatitis A were all shown to have stronger antibody response than afternoon vaccination[95][96][97]. This was believed originally to be due to cortisol elevation in the morning, but upon investigation no evidence suggested cortisol rhythms were responsible for the optimized morning vaccination response[98]. However, the majority of the reported studies lack data on prior immune status before vaccination, as well as data on other confounding factors, including chronotype and sleep times[96].

Future Directions in Chronotherapy Research

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With ongoing advancements in medical research, several promising future directions are being explored to expand the applications of chronotherapy and enhance its effectiveness across a broader range of conditions.

Despite strong experimental and clinical support, the incorporation of chronopharmacological principles into routine care remains limited. Clinical trials specifically designed to evaluate the timing of drug administration are still relatively uncommon, though interest is growing as personalized and circadian medicine gain traction. [24]

Two major challenges currently limit the broader implementation of chronotherapy: the ability to accurately assess individual circadian rhythms in clinical settings, and the development of drug delivery systems that can precisely align with these rhythms. Advances in wearable technology, biomarker identification, and time-controlled drug release systems are being pursued to overcome these barriers and make chronotherapy more personalized and widely applicable[99].

Personalized Chronotherapy

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Advancements in chronobiology suggest tailoring treatment schedules to individual circadian rhythms could optimize therapeutic outcomes. This approach may involve developing diagnostic tools to assess a patient's biological clock and customize interventions accordingly[100].

Integration of Chronotherapy in Oncology

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Emerging evidence indicates that the timing of cancer treatments, such as immune checkpoint inhibitors, can significantly affect their efficacy, along with their side effects[7]. Further research is needed to understand when the optimal time for administration is, and why this is the case for certain mechanisms.

Hypertension Management

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Some studies have explored the benefits of aligning antihypertensive drug administration with circadian blood pressure circulation[101]. Ongoing research on this topic seeks to clarify the clinical implications and optimize treatment protocols to improve precision and localization.

Development of Chrono-Tailored Drug Delivery Systems

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Innovations in drug delivery, including implantable devices and controlled-release formulations, aim to synchronize medication release with circadian rhythms[99]. These technologies could improve treatment effectiveness for various conditions, particularly neurological disorders[102].

See Also

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References

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Category:Wikipedia Student Program

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