Kapadia et al., IJPSR, 2020; Vol. 11(5): 2018-2026.

E-ISSN: 0975-8232; P-ISSN: 2320-5148

IJPSR (2020), Volume 11, Issue 5 (Review Article)

Received on 07 August 2019; received in revised form, 28 November 2019; accepted, 03 April 2020; published 01 May 2020

CHRONOPHARMACOLOGY: THE BIOLOGICAL CLOCK

Salman Kapadia, Vanita Kanase *, Shalaka Kadam, Priya Gupta and Vishwavibhushitam Yadav
Department of Pharmacology, Oriental College of Pharmacy, Sanpada, Navi Mumbai - 400705,
Maharashtra, India.
Keywords: ABSTRACT: Chronopharmacology is the science that is of different types in the
pharmacological activities of different treatment over organic timings and
Chronopharmacology, Chrono-
endogenous balance. Chronotherapeutics is the science which increases the creativity
biology, Chronopharmacokinetics,
and security of prescriptions by balancing their fixations during the 24 h
Chronopharmacotherapy,
synchronizing with regular routine determinants of disease. Chronopharmacokinetics
Circadian rhythm
again manages time and predictable changes in pharmacokinetic parameters of
Correspondence to Author: medicines. For example manages the examination of the fleeting changes in the
Dr. (Mrs.) Vanita Kanase assimilation, dissemination, digestion, and disposal because of the time of planning
Head of Department, of the treatment. Circadian rhythms are especially notable in drugs. Biologic
Department of Pharmacology, rhythms are the endogenic nature of circadian. Chronopharmaceutics is depicted as a
Oriental College of Pharmacy, part of pharmaceutics gave to the plan and evaluation of medication prescribing
Sanpada, Navi Mumbai - 400705, structure that discharges a bioactive specialist at a musicality that preferably
Maharashtra, India. coordinates the natural prerequisite of given disease treatment. The fresher treatment
conveyance structure that is structured with the chronopharmacological approach
E-mail: vanita.kanase@gmail.com holds incredibly long for conveying better patient consideration regarding viability,
resistance, and wellbeing parameters of the medication.

INTRODUCTION: Chronopharmacology is the Chronopharmaceutics Drug Delivery System

discipline that states how the effect of treatment
changes with time and endogenous regularity. The
objective is to improve our comprehension of
intermittent and consequently predictable changes
in both wanted impacts Chrono adequacy and
Chrono resistance of prescriptions 1. Chrono-
pharmaceutics is a part of pharmaceutics (science
and innovation of medication measurement shapes)
intended to the plan and assessment of drugs
movement structure that discharges a bioactive
specialist at a mood that in a perfect world matches
the organic necessity for a given disorders
treatment or counteractive action continuously.
QUICK RESPONSE CODE
DOI:
10.13040/IJPSR.0975-8232.11(5).2018-26
The article can be accessed online on
www.ijpsr.com
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.11(5).2018-26
utilizes the essential ideas of human chronobiology
and the beat reliance on certain sickness states and
the pharmacodynamics of prescriptions 2. Chrono-
pharmacokinetics is characterized as dosing time
dependent on what is more, unsurprising rhythm
varieties in parameters used to describe the
pharmacokinetics of therapy 3. Chronopharma-
cokinetics of a particular medication may comprise
changes from a mono-to a multi-compartmental
model as a component of drug dosing time 4.
Chronopharmacokinetics of medications have been
approved for some, species including people, with
both intense and mild organization even for
continued discharge arrangements having a half-
life (t½) up to 84 h 5. Chronotherapeutics is the
control worried about the movement of medications
as per the inborn exercises of sickness over a
specific timeframe on the grounds that the
biochemical, physiological, and neurotic varieties
over a 24 h period in people have happened 6. The
science managing with the occurrence of organic

International Journal of Pharmaceutical Sciences and Research 2018

Kapadia et al., IJPSR, 2020; Vol. 11(5): 2018-2026.
rhythmicity in living life form is called
chronobiology. The branch controlling the
pharmacological parts of chronobiology is named
as Chronopharmacology, which might be
subdivided into chronotherapy, chronopharma-
cokinetics, and Chrono poisonous quality 7.
Chronotherapeutics includes a treatment strategy
wherein in-vivo medication accessibility is
coordinated to coordinate rhythms of sickness so as
to improve remedial results and prevent symptoms.
It depends on the idea that there is an independent
connection between top to through rhythm
movement in disorders indications and hazards
factors, pharmacologic affectability and
pharmacokinetics of numerous medications take in
to account predictable organization time sub-
ordinate variety in the pharmacokinetics of
medicates just as the weakness because of transient
association of physiochemical process and capacity
of body as circadian and others rhythms 8.
Circadian Rhythm: Circadian rhythm, likewise
called a natural mood, is characterized as motions
in the natural, physiological, and social capacity of
a creature with a periodicity of 24 h. Circadian
rhythms are endogenous in nature and are known to
persevere under free-running conditions. Infections,
for example, hypertension, dead myocardial tissue
(MI), congestive heart disappointment, and stroke,
pursue the body's circadian rhythm 9. It might
likewise be significant in impacting the reactions to
different meds. The malady event is free of time of
day, month, or year. Therefore, the time when meds
are directed is anything but a key concentration for
medicinal services experts in conclusion or
recommending 10. Comprehension of the atomic
control of circadian rhythms and resulting flagging
pathways has taken into consideration new
restorative medication focuses on being recognized.
Thus, a superior comprehension of how to all the
more effectually and securely uses current
medications 11. A consistent combination of
medicines is an accepted method for accomplishing
steadiness in helpful impact and medication
wellbeing 12.
Clinical investigations demonstrate that the extent
of the anticipated in-time (musical) contrasts can be
incredible to the point that it tends to be a solid
determinant of time during 24 h, serious sullen and
mortal occasions happen and when the indications
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E-ISSN: 0975-8232; P-ISSN: 2320-5148
and indications of numerous unending ailments
flare. Thus, circadian time must be considered as a
significant variable affecting a medication's
pharmacokinetics and its belongings or symptoms
13
.
Biologic rhythms are the endogenous nature of
circadian. The absence of outer synchronizers
prompts free-running rhythms. The time of free-
running rhythms is longer or shorter than 24 h and
is a trademark for every species. Our inner
timekeepers are hereditarily determined 14.
Circadian checks are available in many creatures
and negotiate the transaction between the earth;
furthermore, physiologic procedures 15. Typically,
rhythms modify physiologic reactions to foreseen
boosts times. Interruption of circadian rhythms
worsens a few endless sicknesses. The "focal"
circadian pacemaker is in the suprachiasmatic core
in the nerve center and is in charge of organic
rhythms managed by the light / dull cycle (LDC).
Fringe tissues show circadian motions that are
facilitated by the focal pacemaker 16.
Most, if not all, light-touchy creatures, including
warm-blooded animals, have an ace circadian clock
that manages physiological and social procedures
in arrangement with the 24-h day. Late advances in
understanding the atomic control of circadian
rhythms and ensuing flagging pathways have taken
into account new remedial focuses to be recognized
as the ability of how to all the more viably use of
recent medications. Notwithstanding assuming a
key job in typical physiology and conduct,
distortions in the circadian mood are related to the
pathophysiology of sicknesses, including diabetes,
cardiovascular ailment, mental scatters, and
different immune system maladies/inflammation 17-
21
.
Circadian Immune Regulation: A second
unmistakable pharmacological focus with solid
circadian guidelines is the resistant framework. Be
that as it may, late research demonstrates that cell-
self-sufficient timekeepers inside insusceptible
cells themselves direct variety in an extensive
number of circadian safe parameters. For instance,
the reaction of T-cells to encourage shifts in
circadian design 22 and macrophages; thus, revive
insusceptible reactions in similarly diurnal design
with their own rhythm. 23
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The outcomes of the inescapable circadian
guideline of invulnerable capacity are various and
run a long ways past the previously mentioned
diurnal variety in infective weakness. For instance,
an articulated circadian movement of blood
coagulating has been known for quite some time
and is upheld by circadian variety in components
going from platelet total and bond 24 to genuine
articulation of clotting components like PAI-1 25.
Circadian clock likewise direct course of numerous
invulnerable cells, for example, hematopoietic
immature microorganisms 26 At long last, circadian
resistant guideline brings about diurnal varieties in
related insusceptible parameters like aggravation,
which assumes a solid job in circadian variety in
numerous infections 27.
Chronopharmacotherapy in Various Diseases:
Cardiovascular Disease: Various parts of the
human body locate step by step, and these kinds of
variation cause the development in both infection
state and in plasma steady center 28. Cardiovascular
capacities, for example, pulse and circulatory
strain, show 24 h variety. The frequency of
cardiovascular disorder, for example, intense
myocardial localized necrosis, strokes, and
arrhythmia likewise show clear diurnal movement
since a large portion of these can activate deadly or
serious results. It is critical to clarify the exact
system of the beginning of these infections 29. The
distinctions in examples of sickness among day and
night for the cardiovascular issue, for example,
hypertension, angina, heart assault, abrupt
cardiovascular passing, and stroke, have been
recorded.
The Chronotherapeutics approach gives
progressively exact assurance of when patients are
at most noteworthy hazards and in most noteworthy
need of treatment. For instance – it has regularly
been discovered that the pulse of hypertensive
patient increments quickly in the first part of the
day in the wake of enlivening, commonly tops in
the center to late time, diminishes at night, and is
most reduced while the patient rests around
evening time. It might likewise be essential to
perceive that the danger of heart assault gives off
an impression of being most prominent during the
early morning hours in the wake of enlivening. For
example, hair-like opposition and vascular
reactivity are higher toward the beginning of the
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day and diminishes later in the day. Platelet
suitability is expanded, and fibrinolytic movement
is died in the first part of the day, prompting a
condition of relative hypercoagulability of the
blood. Heartbeat is minimal during medication, and
it rises during the early morning time. Numerous
antihypertensive medications do not control the
early morning pulse when given once every day
promptly toward the beginning of the day
Common onset Time of Cardiovascular System:
Disease : Common on the set
of time
Atrial fibrillation : Morning/ night
Ventricular tachycardia : Morning
/ fibrillation
Acute coronary : Early morning
syndrome
Asthma: It is portrayed by airway route
aggravation coming about in hyperresponsiveness
of lower respiratory tract to different natural
upgrades. Airway route opposition increments
dynamically during the evening in the patient.
Asthma is a very famous sickness wherein the wide
circadian variety happens regarding time. There is
an expanded rate of asthma during the early-
morning h. The manifestations of asthma happen
50 to multiple times more during the evening.
The fuel of asthma during the night speaks to the
changing status of natural working because of
circadian rhythms in bronchial patency; airway
routes are hyperactive to acetylcholine, histamine,
and house residue and plasma cortisol, epinephrine,
histamine, and cyclic AMP. When day by day
dosing of breathed in glucocorticosteroid
ciclesonide, supported discharge theophylline,
transdermal tulobuterol fix observed to be powerful
if there should arise an occurrence of nighttime
asthma 30.
Cancer: Human and creature studies recommend
that chemotherapy might be increasingly powerful
and less harmful if malignancy medications are
directed cautiously at chosen times that exploit
tumor cell cycles while less poisonous to ordinary
tissue. The rhythm circadian changes in the tumor
bloodstream and malignant growth development
are significant both when tumors are little and
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Kapadia et al., IJPSR, 2020; Vol. 11(5): 2018-2026.
becoming most quickly and when they are bigger
and developing all the more gradually.
Circadian chemotherapy timing genuinely
influences sedative effect examples and
seriousness, most extreme infected portion, normal
portion power, tumor reaction standard, and the
outlast of a sufferer with malignant swelling.
The pharmacologic and pharmacokinetic properties
of the medication, rhythm changes in DNA and
RNA blend, RNA translational action and mitotic
movement may impact tumor cell vulnerably. The
disease chronogenetic treatment is observed to be
powerful in tumour concealment in-vivo. For
instance, it has been demonstrated that CLOCK
qualities direct affectability of the anticancer
medication cyclophosphamide 31, 32.
Peptic Ulcer: Huge numbers of the elements of the
gastrointestinal tract are liable to circadian
rhythms: corrosive gastric discharge is more during
the evening. While gastric, little inside motility and
gastric exhausting are all slower around evening
time. Concealment of night time erosive is a
significant factor in duodenal ulcer treatment.
Along these lines, for dynamic duodenal ulcer,
when every day at sleep time is the prescribed dose
routine for H2 adversaries. Sleep time H2‐ receptor
bar uses Chronotherapy rhythm issues of supported
or significant decrease of 24‐ h intragastric
sharpness, including the risk of enteric
contamination 33.
Diabetes: In sort, I diabetes the circadian
musicality of insulin, and its development is of
physiologic interest and clinical superiority. In this
way, insulin is discharged in pulsatile style;
however, once in a while; it is periodic. Insulin can
exhibit its circadian rhythm of 8-30 min, which can
display its perfect activity.
The modulators of insulin discharge and activity
are emitted in a circadian example and attract the
method of insulin discharge. So contrast among
most extreme and least plasma insulin fixation has
transient rhythmicity, and complex optional
circadian musicality is variable early-morning and
late-evening insulin obstruction 34.
Chronopharmacology of Arthritis: Rheumatoid
arthritis (RA), osteoarthritis (OA), ankylosing
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spondylitis (AS), and gout exhibit profound
circadian rhythm in manifestations and intensity of
symptoms.
A. Rheumatoid Joint Inflammation (RA): It is a
continuous blazing immune system issue with
indications of solidness, swelling, and trauma of at
least one joint. The severity of these is multiple
times more somewhere in the range from 08:00 to
11:00 am. Long-acting NSAIDs like flurbiprofen,
ketoprofen, indomethacin at sleep time guarantee
satisfactory control of morning indications of RA.
Ibuprofen, non-acetylated salicylates, and various
other nonsteroidal anti-inflammatory drugs
(NSAIDs) are utilized in rheumatoid joint pain
(RA) patients to diminish joint aggravation and
improve work. Proportionate dosages of ibuprofen
and of non-acetylated salicylates are similarly
mitigating in RA 35.
B. Pain is Increasingly Extreme Between 2 p.m.
What's More, 8 pm: The torment for some
timeframe fluctuates from individual to person. If
when the agony is more around night time, evening
segment is endorsed at this point in case injury is
most horrible in the night, morning bit is proposed.
Individualized chronotherapy is fundamental, as
once per day ketoprofen, indomethacin is
prescribed to time of day when trauma is most
exceedingly terrible. Strong scattering of
ketoprofen was observed to be increasingly
powerful in the hindering movement of RA. The
defensive impact of ketoprofen and its strong
scattering was fundamentally higher when these
were regulated at 0800 h 36.
Need for Chronopharmacotherapy: Chrono-
pharmacology is required to screen treatment in
order to restrain the term of treatment, particularly
in situations where patients are as of now having
bargained renal, heart, and hepatic or some other
capacity of the body. Any sort of collection of
medications in these organs causes more
noteworthy harmfulness, which may be prompted
to reduce the capacity of the organ. In this manner,
chronopharmacotherapy turns into a significant
piece of the treatment of a few infections,
especially those affecting focused on body parts 37.
As per the 1996 American restorative affiliation
survey, more thought of chronotherapy in clinical
preliminaries is exceptionally invited by the entire
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medicinal network. The aftereffect of the review
demonstrated that 75 percent of the specialists are
agreeable to the patient's circadian or day by day
rhythm arranged treatment 38.
From the different examinations, it is shaped that
numerous cardiovascular occasions, including
myocardial dead tissue, stroke, and unexpected
passing, happen during the underlying long periods
of morning movement between 6 am, which is
more, 12 noon afternoon. Furthermore, this is a lot
higher during this period than other planning
during the day. Circulatory strain demonstrates a
sharp top in the early morning, significantly
agreeing with the crest for cardiovascular occasions
and a stretched out during the night 39. In the
meantime, pulse increments in the late morning or
early evening 40. In our investigation, most extreme
doctors were recommending the drug as
chronopharmacologically it can profit the patient
however to the extent PPIs (Proton pump
inhibitors) were concerned doctor endorsed them
before breakfast as opposed to endorsing it at sleep
time. This demonstrates the chronopharmacological
approach is yet to be implemented in the clinical
practice.
Chronopharmacokinetics:
Absorption: In people, for orally directed
medications, assimilation was demonstrated to be
influenced by circadian rhythm as corrosive gastric
emission and gastric pH, gastric motility,
exhausting gastric time, and gastrointestinal
bloodstream change as indicated by the season of
day 41, 42. These progressions may affect the time-
subordinate distinction of medication assimilation.
Then again, exhausting gastric time is another
significant factor in the retention of medications.
Gastric eradication rates were thought about
between 8:00 am to 8:00 pm in male subjects, and
it was discovered that gastric discharging (t½) for
the night supper was essentially longer for solids
yet not for fluids contrasted and those of the
morning meal 43.
The expansion in night meal gastric discharging
time may likewise cause a postponement in
achieving top plasma fixations for a few
medications. Such varieties might be identified
with the physicochemical properties of a
medication, since most lipophilic medications
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appear to be consumed quicker in the first part of
the day when contrasted with night 44, 45. The
systems basic the chronokinetics of lipophilic
medications include a quicker gastric discharging
time and higher gastrointestinal perfusion in the
first part of the day 46.
Distribution: In natural liquids and tissues,
circadian changes identified with medication
dispersion are appeared to change as per the time of
day 47. Bloodstream relies upon a few
administrative elements, including the thoughtful
and parasympathetic frameworks whose exercises
are known to be circadian time-dependent with a
dominating diurnal impact of the thoughtful
structure 48. Therefore, daytime increments and
evening diminish the bloodstream, and nearby
tissue bloodstreams may clarify a conceivable
contrast in medication appropriation relying upon
dosing time 49, 50.
Most human plasma protein fixations, including
egg whites and a1-glycoprotein, collapse down to
their least during the evening time, increment by
day, and reach to most around early afternoon.
Subsequently, everyday varieties have been
accounted for medication protein authoritative.
Touitou et al., (1986) have demonstrated that in
youthful solid grown-up subjects, the circadian
abundance of plasma protein was fairly little (8-
15%) contrasted and that of sound old subjects
(normal age ~ 75 yr).
A noteworthy night time fall was watched for the
last mentioned (circadian adequacy of 20%), an
outcome which recommends that the free part of
medications typically bound to plasma proteins
increments during the nighttime rest as a
component of maturing 51. The impacts of circadian
rhythm on the plasma protein authoritative of
medications were first shown for cortisol, which
spans to its most noteworthy level around early
afternoon.
Moreover, the engineered analogs for cortisol were
indicated to be impacted by circadian mood 52, 53.
P-glycoprotein, the result of the multidrug
opposition (MDO) quality which adds to renal,
biliary and intestinal disposal of medications, and
the intestinal H(+) / peptide co-transporter 1
(PEPT1) assume significant jobs as a supplement
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and medication transporter work as a xenobiotic
transporter and display 24 h variety 54, 55. From a
toxicological perspective, drugs with a little
volume of dissemination and additionally high
protein-restricting limit and medications which
have a tight remedial record might be influenced by
the progressions in circadian rhythm and wrong
dosing of such medications in evening time may
cause direct lethality.
Metabolism: Hepatic medicines digestion appears
to rely upon liver xenobiotic-using protein
movement or potentially hepatic bloodstream 56, 57.
Circadian rhythm can influence the bloodstream in
the liver and, in this way, can influence the liberty
of a few medications, including propranolol 58. In
well-evolved creatures, a large portion of the
xenobiotics is utilized in, for the most part, in the
liver. Be that as it may, there is moreover
extrahepatic metabolism in the cerebrum, kidney,
lung, and different tissues. Xenobiotic digestion is
made out of three gatherings of proteins with
unmistakable capacities. The stage I gathering
contains the microsomal cytochrome P450
(CYP450) catalysts. Stage II, or conjugating
compounds, involves sulfotransferases (SULT),
UDP-glucuronotransferases (UGT), NAD (P) H
quinine oxidoreductases (NQO), epoxide
hydrolases (EPH), glutathione-S-transferases
(GST) and N-acetyltransferases (NAT).
Conjugation gives the lipophilic mixes to be
hydrophilic enough in this way control and
encourage their discharge into bile, feces, and
additionally urine.
After stage II reactions, the xenobiotic conjugates
can apply to organize III reactions 59, 60, 61. Few
kinds of oxidative reactions catalyzed by the
CYP450 compounds been accounted for substrates,
for example, aminopyrine, paranitroanisole,
hexobarbital and 4-dimethy-aminobenzene, aniline,
benzphetamine, benzpyrene and imipramine 62, 63. It
appears that medication digestion coming because
of oxidative microsomal responses achieves its
crest during the action range and it's most minimal
during the relaxation period. On the contrary,
sulfate conjugations are a lot faster during rest than
during the action period 64.
Excretion: The circadian planning framework
assumes a key job in the progressions of the
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lethality of medications by affecting their digestion
systems in the liver and digestive system,
notwithstanding their discharge by means of bile
stream and urine. Rodents with endless biliary
waste under an unbending lighting plan (light on at
6 am and off at 6 pm) displayed a noteworthy
circadian rhythm of bile stream, biliary obsession,
and evacuative amount of bile salts, cholesterol and
phospholipids 65. Then again, the discharge rates of
these polyamines were found to be most elevated
toward the beginning of the day in sound volunteer
subjects 66. A gigantic decrease in the rate and level
of ciprofloxacin release following 10 pm
association was distinguished 67. The excretion of
17-oxosteroids was likewise indicated to be
impacted by circadian clock 68.
Advantages of Chronopharmacotherapy:
1. It counteracts an overdosing of any class of
medication.
2. It makes the use of the medication
progressively proper, and in this manner, the
estimation of a medication is expanded.
3. It decreases the symptoms of medication and
aides in minding out the treatment for just a
specific or constrained timeframe 69.
Disadvantages of Chronopharmacotherapy:
1. It builds up a non 24 h rest wake disorder
after the treatment as the individual doses for
more than 24 h during the treatment. It's not
exactly normal, but rather, the level of hazard
is not known.
2. An individual may likewise be denied of rest
now and then.
3. The individual turns out to be less profitable
during chronotherapy and remaining alert till
the other timetable may be a bit awkward.
4. The patient should take a break from the busy
schedule calendar as its time taking
treatment.
5. Therapeutic supervision is compulsory for
this treatment, and customary counseling of
rest pros is prescribed.
6. Individual needs to keep himself wakeful till
the following rest plan so he needs to get
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himself occupied with the goal that he
remains alert till the other calendar.
7. Individuals experiencing treatment may feel
curiously hot or cold now and then.
8. Patient needs to counsel the specialist
routinely to prevent reactions 70, 71.
Ideal Characteristics of Chronopharmaco-
therapy:
1. It is non-toxic inside affirmed cut-off points
of utilization.
2. It should have a real‐ time and explicit
activating biomarker for a given ailment
state.
3. It ought to have a criticism control
framework (for example, self-regulated an
adaptative capacity to circadian mood and
individual patient to separate between
conscious – rest status).
4. It is Biocompatible and biodegradable,
particularly for the parenteral organization.
5. It is Simple to fabricate at the financial
expense.
6. It is Simple to control into patients so as to
upgrade consistency to measurement routine 72.
CONCLUSION: The importance of this article is
to educate scholars, physicians, pharmaceutical
researchers, and other experts about the seriousness
of organic timekeepers and Chronopharmacology
to human wellbeing and infection additionally
inspire the agent to grow new devices for the
treatment of various maladies. The regularly
growing field of chrono-pharmacology has opened
numerous entryways in innovative work for
structuring better approaches to adjust and oversee
the treatment for different illnesses. So, as to make
an interpretation of research information into
clinical application, noteworthy advancement in the
portrayal of circadian varieties in protein
articulation and action in people is totally vital.
In this manner, the information of chrono-
pharmacology isn't constrained to the scholars,
pharmacologists and researchers yet in addition to
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clinicians so that there is the better conveyance of
patient consideration.
ACKNOWLEDGEMENT: The author thanks his
guide Dr. (Mrs.) Vanita Kanase for constantly
supporting and every colleague who supported
during the work.
CONFLICTS OF INTEREST: No conflicts of
interest between any of the authors.
REFERENCES:
1. http://www.annualreviews.org/doi/abs/10.1146/annurev.pa
.32.040192.000411?journalCode=pharmtox.
2. Patel G: Specialized chronotherapeutic drug delivery
systems, Pharmainfo.net
3. Ohdo S, Koyanagi S, Matsunaga N and Hamdan A:
Molecular basis of chronopharmaceutics. J Pharm Sci
2011; 100: 3560-76.
4. Baraldo M: The influence of circadian rhythms on the
kinetics of drugs in humans. Expert Opin Drug Metab
Toxicol 2008; 4: 175-92.
5. Ohdo S, Koyanagi S, Matsunaga N and Hamdan A:
Molecular basis of chronopharmaceutics. J Pharm Sci
2011; 100: 3560-76.
6. Sarasija S and Hota A: Colon-specific drug delivery
systems. Ind J Pharm Sci 2002; 62(1):1-8.
7. Pandit V and Suresh S: Emerging role of biorhythms in
optimizing treatment of disease. Indian. J Novel Drug
Delivery 2009; 1: 2-10.
8. Devdhawala MG and Seth AK: Current status of
Chronopharmatherapeutic drug delivery system: an
overview. J Chem Res 2010; 2(3): 312-28.
9. Mehul DG and Avinash SK: Current status of chrono-
therapeutic drug delivery system: an overview. J Chem
Pharm Res 2010; 2: 312-28.
10. Smolensky MH, Lemmer B and Reinberg AE:
Chronobiology and chronotherapy of allergic rhinitis and
bronchial asthma. Adv Drug Deliv Rev 2007; 59: 852-82.
11. Ohdo S: Biological clock and chronopharmacology. Nihon
Shinkei Seishin Yakurigaku Zasshi 2007; 27: 95-02.
12. Reinberg A: Clinical chronopharmacology. Concepts,
kinetics, application. Br J Clin Pharmacol 1991; 32: 255.
13. Smolensky MH, Peppas NA: Chronobiology, drug
delivery and chronotherapeutics. Adv Drug Deliv Rev
2007; 59: 828-51.
14. Fujimura A Tateishi T, Ohashi K and Ebihara A:
Differences of chronopharmacokinetic profiles between
propranolol and atenolol in hypertensive patients. J Clin
Pharmacol 1993: 756-61.
15. Hogenesch JB and Herzog ED: Intracellular and
intercellular processes determine robustness of the
circadian clock. FEBS Lett 2011; 585: 1427-34
16. Mohawk JA, Green CB and Takahashi JS: Central and
peripheral circadian clocks in mammals. Annu Rev
Neurosci 2012; 35: 445-62.
17. Rybak YE, McNeely HE, Mackenzie BE, Jain UR and
Levitan RD: Compr Psychiatry 2007; 48: 562.
18. Levi F and Schibler U: Annu Rev Pharmacol Toxicol
2007; 47: 593.
19. Solt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ,
Lundasen T, Shin Y, Liu J, Cameron MD, Noel R, Yoo S-
2024
Kapadia et al., IJPSR, 2020; Vol. 11(5): 2018-2026.
H, Takahashi JS, Butler AA, Kamenecka TM and Burris
TP: Nature 2012; 485: 62.
20. Ohdo S: Biol Pharm Bull 2010; 33: 159.
21. Sprouse J: Expert Opin Ther Targets 2004; 8: 25.
22. Fortier EE, Rooney J, Dardente H, Hardy MP, Labrecque
N and Cermakian N: Circadian variation of the response of
T cells to antigen. J of Immunology 2011; 187: 6291-00.
23. Keller M, Mazuch J, Abraham U, Eom GD and Herzog
ED: A circadian clock in macrophages controls
inflammatory immune responses. proceedings of the
National Acad of Sci of the USA 2009; 106: 21407-12.
24. Fujimura A, Ohashi K and Ebihara A: Daily variations in
platelet aggregation and adhesion in healthy subjects. Life
Sciences 1992; 50: 1043-7.
25. Kluft C, Jie AF, Rijken DC and Verheijen JH: Daytime
fluctuations in blood of tissue-type plasminogen activator
(t-PA) and its fast-acting inhibitor (PAI-1). Thrombosis
and Haemostasis 1988; 59: 329-32.
26. Mendez-Ferrer S, Lucas D, Battista M and Frenette PS:
Haematopoietic stem cell release is regulated by circadian
oscillations. Nature 2008; 452: 442-7.
27. Scheiermann C, Kunisaki Y and Frenette PS: Circadian
control of the immune system. nature reviews.
Immunology 2013; 13: 190-8.
28. Singh R, Sharma PK and Malviya R: Review on
chronopharmaceutices - a new remedy in the treatment of
various diseases. Euro J Biological Sci 2010; 2(3): 67-76.
29. Patel B, Prajapati P and Patel C: Chronopharmacolgy and
chronopharmaceutical of cardiovascular disease. Res J
Pharma Bio Chem Sci 2011; 2(2): 740-483.
30. Martin RJ and Banks-Schlegel S: Chronobiology of
asthma. Am J Respir Crit Care Med 1998; 158: 1002-07.
31. Hori K, Zhang QH, Li HC, Saito S and Sato Y: Timing of
cancer chemotherapy based on circadian variations in
tumor tissue blood flow. Int J Cancer 1996; 65: 360-64.
32. Levi V: Circadian chronotherapy for human cancers.
Lancet Oncol 2001; 2: 307-15.
33. Humphries TJ, Root JK and Hufnagel K: Successful drug
specific chronotherapy with the H2 blocker famotidine in
the symptomatic relief of gastro-esophageal reflux disease.
Ann New York Acad Sci 1991; 517-18.
34. Cincotta AH and Meier AH: Circadian rhythms of
lipogenic and hypoglycaemic responses to insulin in the
golden hamster. J Endocrinol 1984; 103: 141-46.
35. Satyanarayana V and Krishnan P: Chronopharmacology:
tailoring therapy to endogenous rhythms. Journal of
International Medicine and Dentistry 2015; 2 (1): 03-16.
36. Menet JS, Rodriguez J, Abruzzi KC and Rosbash M:
Nascent-Seq reveals novel features of mouse circadian
transcriptional regulation. eLife 2012; 1:e00011.
37. Koppiseti VS and Sunalatha SH: Chronopharmacologly
and chronopharmacotherapy-a guide to better health. Res J
Pharma Bio and Chem Sci 2011; 2: 266-28.
38. Sharma D and Malhotra, P: Chronopharmacology and drug
prescribing pattern of physicians in a tertiary care hospital
of North India. International Journal of Basic & Clinical
Pharmacology 2018; 7(3), 499-502.
39. Lago A, Geffner D, Tembl J, Landete L, Valero C and
Baquero M: Circadian variation in acute ischemic stroke: a
hospital-based study. Stroke; A Journal of Cerebral
Circulation 1998; 29: 1873-5.
40. David SHG: Pharmacology of cardiovascular chrono-
therapeutics agents. AJH 2001; 14: 296-01.
41. Lee YC, Wang HP, Lin LY, Chuang KJ, Chiu HM and Wu
MS: Circadian change of cardiac autonomic function in
correlation with intra-esophageal pH. J Gastroenterol
Hepatol 2006; 21: 1302-8.
International Journal of Pharmaceutical Sciences and Research
E-ISSN: 0975-8232; P-ISSN: 2320-5148
42. Konturek PC, Brzozowski T and Konturek SJ: Gut clock:
Implication of circadian rhythms in the gastrointestinal
tract. J Physiol Pharmacol 2011; 62: 139-50.
43. Hershcovici T, Jha LK, Cui H, Powers J and Fass R:
Night-time intra-oesophageal bile and acid: A comparison
between gastrooesophageal reflux disease patients who
failed and those who were treated successfully with a
proton pump inhibitor. Ali Pharma Ther 2011; 33: 837-44.
44. Baraldo M: The influence of circadian rhythms on the
kinetics of drugs in humans. Expert Opin Drug Metab
Toxicol 2008; 4: 175-92.
45. Fischer TW, Greif C, Fluhr JW, Wigger-Alberti W and
Elsner P: Percutaneous penetration of topically applied
melatonin in a cream and an alcoholic solution. Skin
Pharmacol Physiol 2004; 17: 190-4.
46. Konturek PC, Brzozowski T and Konturek SJ: Gut clock:
implication of circadian rhythms in the gastrointestinal
tract. J Physiol Pharmacol 2011; 62: 139-50.
47. Labrecque G and Bélanger PM: Biological rhythms in the
absorption, distribution, metabolism and excretion of
drugs. Pharmacol Ther 1991; 52: 95-07.
48. Anderson NH, Devlin AM, Graham D, Morton JJ,
Hamilton CA and Reid JL: Telemetry for cardiovascular
monitoring in a pharmacological study: new approaches to
data analysis. Hypertension 1999; 33: 248-55.
49. Stow LR and Gumz ML: The circadian clock in the
kidney. J Am Soc Nephrol 2011; 22: 598-04.
50. Innominato PF, Lévi FA and Bjarnason GA:
Chronotherapy and the molecular clock: Clinical
implications in oncology. Adv Drug Deliv Rev 2010; 62:
979-01.
51. Touitou Y, Touitou C, Bogdan A, Reinberg A, Auzeby A
and Beck H: Differences between young and elderly
subjects in seasonal and circadian variations of total
plasma proteins and blood volume as reflected by
hemoglobin, hematocrit and erythrocyte counts. Clin
Chem 1986; 32: 801-4.
52. Stow LR and Gumz ML: The circadian clock in the
kidney. J Am Soc Nephrol 2011; 22: 598-04.
53. Innominato PF, Lévi FA and Bjarnason GA:
Chronotherapy and the molecular clock: Clinical
implications in oncology. Adv Drug Deliv Rev 2010; 62:
979-01.
54. Ando H, Yanagihara H, Sugimoto K, Hayashi Y, Tsuruoka
S and Takamura T: Daily rhythms of P-glycoprotein
expression in mice. Chronobiol Int 2005; 22: 655-65.
55. Murakami Y, Higashi Y, Matsunaga N, Koyanagi S and
Ohdo S: Circadian clock- controlled intestinal expression
of the multidrug-resistance gene mdr1a in mice.
Gastroenterology 2008; 135: 1636-44.
56. Ohdo S: Changes in toxicity and effectiveness with timing
of drug administration: Implications for drug safety. Drug
Saf 2003; 26: 999-010.
57. Smolensky MH: Circadian rhythms in medicine. CNS
Spectra 2001; 6: 467-74, 479-82.
58. Alvarez D, de las Heras M, Abecasis R, Terg R, Gerona S
and Albornoz L: Daily variation in portal blood flow and
the effect of propranolol administration in a randomized
study of patients with cirrhosis. Hepato 1997; 25: 548-50.
59. Xu C, Li CY and Kong AN: Induction of phase I, II and III
drug metabolism/transport by xenobiotics. Arch Pharm
Res 2005; 28: 249-68.
60. Homolya L, Váradi A and Sarkadi B: Multidrug resistance
associated proteins: export pumps for conjugates with
glutathione, glucuronate or sulfate. Bio 2003; 17: 103-14.
61. König J, Nies AT, Cui Y and Keppler D: Conjugate export
pumps of the multidrug resistance protein (MRP) family:
2025
Kapadia et al., IJPSR, 2020; Vol. 11(5): 2018-2026. E-ISSN: 0975-8232; P-ISSN: 2320-5148

Localization, substrate specificity and MRP2-mediated human subjects. Antimicrob Agents Chemother 1997; 41:
drug resistance. Bioc Biophys Acta 1999; 1461: 377-94. 1802-4.
62. Bass J and Takahashi JS: Circadian integration of 68. Ghiciuc CM, Cozma-Dima CL, Pasquali V, Renzi P,
metabolism and energetics. Science 2010; 33: 1349-54. Simeoni S and Lupusoru CE: Awakening responses and
63. Bellet MM and Sassone-Corsi P: Mammalian circadian diurnal fluctuations of salivary cortisol, DHEA-S and a-
clock and metabolism - the epigenetic link. J Cell Sci amylase in healthy male subjects. Neuro Endocrinol Lett
2010; 123: 3837-48. 2011; 32: 475-80.
64. Hoffman DA, Wallace SM and Verbeeck RK: Circadian 69. Rajkumar LA and Kumar SV: Evaluation of
rhythm of serum sulfate levels in man and acetaminophen chronosensitivity and Chronopharmacology of some
pharmacokinetics. Eur J Clin Pharmacol 1990; 39: 143-8. centrally acting potential drugs in albino Wistar rats.
65. Lo Sasso G, Petruzzelli M and Moschetta A: A Scholars Research Library 2010; 1(4): 52-56
translational view on the biliary lipid secretory network. 70. Martin RJ and Banks-Schlegel S: Chronobiology of
Biochim Biophys Acta 2008; 1781: 79-96. asthma, Am J Respir Crit Care Med. 1998; 158: 1002- 07.
66. Pöyhönen MJ, Uusitalo UM, Kari A, Takala JA, 71. Muller JE, Tofler GH and Stone PH: Circadian variation
Alakuijala LA and Eloranta TO: Urinary excretion of and triggers of onset of acute cardiovascular disease.
polyamines: Importance of circadian rhythm, age, sex, Circulation 1989; 79: 733-43.
menstrual cycle, weight and creatinine excretion. Am J 72. Singh S, Singh S, Singh Y, Gupta D, Saxena P, Gupta S,
Clin Nutr 1990; 52: 746-51. Singh A and Srivastva A: Chronopharmacology: recent
67. Rao VV, Rambhau D, Rao BR and Srinivasu P: Circadian advancements in the treatment of diabetes mellitus through
variation in urinary excretion of ciprofloxacin after a chronotherapy. International Journal of Pharmacy and
single-dose oral administration at 1000 and 2200 hours in Pharmaceutical Sciences 2017; 9: 87-99.

How to cite this article:

Kapadia S, Kanase V, Kadam S, Gupta P and Yadav V: Chronopharmacology: the biological clock. Int J Pharm Sci & Res 2020; 11(5):
2018-26. doi: 10.13040/IJPSR.0975-8232.11(5).2018-26.
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