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About Authors:
Rawat Smriti*, Bisht Seema, Kothi Yal Preeti
Shri Guru Ram Rai Institute of Technology & Sciences
Dehradun, Uttarakhand, India.

Many human biological processes are regulated by circadian rhythms, which follow 24-h cycles and involve the neuroendocrine and immune systems. There is strong evidence for an impact of circadian rhythms in the symptoms of Rheumatoid arthritis, and a number of pro-inflammatory cytokines that exhibit a peculiar rhythmicity in particular serum TNF- α and serum IL-6, and together with other relevant immunological parameters display an elevation in the early morning hours. The increase in nocturnal anti-inflammatory cortisol secretion is insufficient to suppress ongoing inflammation, resulting in the morning symptoms of joint stiffness, pain, and functional disability are characterized.With chronotherapeutics becoming ever more popular, more consideration is being given to the timing of therapy for a number of chronic diseases. The recent surge of interest in the field of chronobiology has highlighted the importance of optimising timing of treatment administration. In this article we discuss the chronobiology of Rheumatoid arthritis and the availability of a new programmed-release.


Most humans have a relatively regular activity pattern (sleep, labor, and meal etc.). This activity can be roughly classified into the rest phase and active phase, and body temperature, heart rate, blood pressure, and the dominance of the sympathetic and parasympathetic nerves differ in each phase. These variations display daily rhythms, which are known as circadian rhythms. Circadian rhythms are self-sustained endogenous oscillations that occur with a periodicity of approximately 24 hours and are regulated by the circadian clock.[1]The term ‘‘circadian’’ was coined by Franz Halberg from the Latin circa, meaning about, and dies, meaning day [2]. The environmental light/dark cycle is the most salient cue influencing these circadian rhythms[3]. These circadian rhythms are also associated with the risk or frequency of disease occurrence. For example, asthma attacks get worse between midnight and early morning and are seldom observed in the daytime. In addition, the risks of spontaneous acute dissection and rupture of the thoracic aorta, myocardial ischemia, ischemic stroke, and subarachnoid hemorrhage are higher during the active phase than during the rest phase. The variations in heart rate, blood pressure, and blood flow, etc., induced by the wake-sleep transition are considered to affect the risk of such problems occurring[4]. Interestingly, pain such as toothache, migraine, and rheumatoid arthritis pain is more acute in the early morning.

Chronotherapeutics, have been developed in close connection with emerging pulsatile delivery views. In this respect, it is well established that the symptoms of many pathologies, as well as the pharmacokinetic and pharmacodynamic profiles of most drugs, are subject to circadian variation patterns. To introduce the concept of chronotherapeutics, it is important to define the following concepts.

Chronotherapy: -[5] Co-ordination of biological rhythms and medical treatment is called chronotherapy.

Chronobiology is thus that discipline which deals with difference in physiology of an individual according to time of day, month or year or even period in one’s life.[6] Endocrine system provides examples illustrating chronobiology, e.g., a range of hormones including cortisol, catecholamines are secreted in morning, whereas hormones like melatonin (MLT), adrenocorticotropic hormone finds their maxima in the evening or during sleep. Priming of these hormones at various durations of the day leads to alteration in body’s physiological functions at various times of the day.[7, 8]

Pharmaceutics is an area of biomedical and pharmaceutical sciences that deals with the design and evaluation of pharmaceutical dosage forms (or drug delivery systems) to assure their safety, effectiveness, quality, and reliability.

Chronopharmaceutical drug delivery systems (ChrDDSs) should embody time-controlled and site-specific drug delivery systems [9]. The delivery of medications – in the right concentration, to the right targeted tissues, at the right time – to meet biological-rhythm.  This technique is thus beneficial to treat diseases like asthma, Rheumatoid arthritis (RA), cardiovascular diseases since they show chronobiological behavior. This methodology also proves beneficial for pathophysiological states where night time dosing is required.[10, 11]

These are the biological process that shows cyclic variation over time. There are three types of Rhythms generally present in the human body, which was shown in Table 1.
A. Circadian Rhythms: “Circa” means about and “dies” means day.
B. Ultradian Rhythms: Oscillation of shorter duration is termed as Ultradian. (More than one cycle/day)
C. Infradian Rhythms: Oscillations those are longer than 24 h. (less than one cycle/day)

The potential benefits of chronotherapeutics have been demonstrated in the management of a number of diseases. In particular there is a great deal of interest in how chronotherapy can particularly benefit patients suffering from allergic rhinitis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, asthma, cancer, cardiovascular diseases, and peptic ulcer disease.

Arthritis (derived from Greek word artho: joint, itis: inflammation), is a condition involving damage to joints of the body. Arthritis may broadly be classified as under:
a) Rheumatoid arthritis (RA)
b) Septic arthritis
c) Juvenile arthritis
d) Ankylosing spondilytis

RA is a disease in which body’s own immune system starts to attack body’s tissue. Immune complex composed of Ig M (Ig: immunoglobulin) activate complement and release cytokines which are chemotactic for neutrophils. These inflammatory cells secrete lysosomal enzymes which damage cartilage and bones, while prostaglandins produced in the process cause vasodilatation and pain.Common symptoms includes varied level of pain, swelling, joint stiffness and sometimes a constant ache around the joints.[20, 21]

Theory regarding pathogenesis of RA
According to theory T-cells may be important in initiating the disease, but chronic inflammation is self perpetuated by macrophages and fibroblasts. Absence of activated

T-Phenotypes in chronic RA and presence of activated macrophage and fibroblast phenotypes lay substance to this theory. At site of inflammation fibroblast of affected cartilage secretes:
i. Cytokines: IL-6, IL-8 (IL: Interleukin)
ii. Prostaglandins
iii. Protease enzyme

Protease and prostaglandins act directly to erode and destroy bones and cartilage thus producing inflammation and other symptoms of arthritis[22, 23]

Circadian rhythm of nocturnal hormones in rheumatoid arthritis:
From decades it had been known that pathological symptoms in RA follow circadian rhythm, with priming of symptoms in early morning, abatement during the noon and then starts increasing from late evening. Serum concentration and release cytokine is triggered by melatonin and other hormones from hypothalamus, and follow a strict 24 h cycle. IL-6 is the most important of all cytokines responsible for pathological symptoms pertaining to RA. Other pro- inflammatory hormones manifesting RA include TNF, IL-1, IL-8, IL-12 and IL-17.20.Positive genetic relationship between melatonin and RA had been reported by the researchers that melatonin (MLT) levels increased progressively from 8 PM to early morning with a peak at midnight. From researches it had been concluded that MLT concentration stimulate the production of interferon γ, IL-1, IL-2, IL-6 etc. in mononuclear cells of blood, moreover MLT enhances production of inflammatory cytokine from human monocytes. Excess concentration of MLT had been reported in synovial fluids of patients having RA, moreover binding sites for MLT were also found to be present in synovial macrophage. It was found that concentration of various cytokine primes during night and early morning just after the stage when MLT serum levels are higher whereas plasma cortisol level the lowest, thus it is concluded that MLT up regulates cytokine production and immune functions, thus leading to joint inflammation, joint stiffness etc. [24-27] Cortisol secretion and glucocorticoids receptor density has been reported to be altered in patients with RA [28, 29]. It was found that increased cortisol synthesis inhibits the rise in concentration of IL-6 in RA patients.

Circadian Rhythms in Rheumatoid Arthritis
In patients with RA, disease symptoms such as joint pain, morning stiffness and functional disability increase in the early morning, with abatement during the day and a smaller new increase in the early evening.[30]Circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids are responsible, in part, for the time- dependent changes observed in the inflammatiory response of RA.[31]

Herold and Günther [32] reported that plasma C-reactive protein (CRP) levels, an indicator of inflammatory responses, showed a circadian rhythm with a peak in the early morning and a trough in the evening in RA patients, which matches the rhythms of pain and stiffness. Proinflammatory cytokines, such as TNF- α and IL-6, are secreted from activated monocytes, and macrophages increase CRP levels in hepatocytes. There are clear circadian rhythms in the blood concentrations of these cytokines, with higher levels seen in the early morning in RA patients [33]. Since the circadian rhythms of CRP and cytokines are similar, it is considered that cytokine rhythms contribute to the rhythm of CRP levels. Among the pro-inflammatory cytokines involved in circadian changes, IL-6 is of particular relevance as its levels most closely follow the daily pattern of RA symptoms. [34, 35]

Circadian Rhythms inOsteoarthritis
The circadian rhythm of pain and stiffness in osteoarthritis differs from that of rheumatoid arthritis. Osteoarthritis is a degenerative disease of the joints and is the commonest of all joint diseases, affecting nearly everyone at least to some degree by age 70. The weight bearing joints of the hip, knee, back, toes a pain of osteoarthritis sufferers is typically less intense in the morning than in the afternoon. The successful treatment of osteoarthritis requires that medications be taken at the right time or evening. The temporal pattern of pain and stiffness in osteoarthritis sufferers differs between persons. Thus, an individualized chronotherapy of NSAIDs is necessary. The chronotherapy of osteoarthritis involves the administration of once-a-day forms of ketoprofen, indomethacin and other such medicines in relation to the time of day pain is worse. If pain is worse at night or early in afternoon, an evening once-a day NSAIDs schedule is recommended. If pain is worse in the afternoon or night, a once-a-day morning or noontime treatment schedule is best, providing the amount of side effects produced by the morning one, in particular, is minimal [36].

Circadian Rhythms inAnkylosing Spondylitis
Ankylosing spondylitis is characterized by swelling and discomfort of the joints of the back. In its occurrence it is an inherited disorder that is more common in men than women. Overall, back stiffness and pain were a problem throughout the 24 h, but pain intensity was rated 2 to 3 times higher and stiffness about 8 times greater between 06:00 and 09:00 am than between noon and 15:00 pm when each was least bothersome. The symptoms also exhibited a second less prominent peak between 19:00 and 21:00 pm. Marked seasonal variation in ankylosing spondylitis was also prominent. The onset of backache and stiffness was 12 times more frequent in winter than summer. Moreover, reoccurrence of back problems occurs 2 to 3 times more often in winter than summer [37, 38].



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