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Ramn C. HermidaLab. Bioing. Cronobiol.

Universidad de Vigo

THEORETICAL AND PRACTICAL

BACKGROUNDfor

CHRONOPHARMACOLOGY

inCARDIOVASCULAR

PATHOLOGY

Conf. Dr. ADRIANA ILIESIU,

Conf. Dr. HORIA BALANUMF CAROL DAVILA


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Universidad de Vigo

JULIEN-JOSEPH VIREY(17751846)

19th

Century

First DOCTORALTHESIS in

CHRONOBIOLOGY

Paris 1814


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Universidad de Vigo

JULIEN-JOSEPH VIREY(17751846)

19thCentury

HE DISCOVERED CHRONOPHARMACOLOGY

"Any medication is not equally indicated

at all clock hours, and here the diurnal

periodicity needs to be taken into account"


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Universidad de Vigo

Lvi , Lan cet Onc ol 2001 ; Mo rmon t & Lvi , Canc er 2003

?

Peripheraloscillators

Proliferation

Metabolism

23 23 7711

Un

its

Time (h)

SCNTRH Melatonin

CNS, ho rmones,

peptides,

neuromediators

PVN

Glutamate

PACAP

Pineal gland

NPY

Central

coordination

TGF, EGF

Prokineticine

Glucocort icoids

Feeding schedules& para sys tems

Circadiantimingsystem

Relevance of circadian biology and therapeutics in elderly cancer patients

Rest-activity rhythm

Circadian physiology


5/28


Universidad de Vigo

Biological rhythmsNeuronal rhythms 0.01-10 s

Cardiac rhythms 1 s

Calcium oscillations 1 s - 30 min

Biochemical oscillations 1-20 min

Mitotic cycle 10 min - 30 h

Circadian rhythms 20 - 28 h

Hormonal rhythms 10 min - 3 h

Ovarian cycle 28 days

Circannual rhythms 1 year

After A Goldbeter in : Bio chemical o sci l lat ions and cel lu lar rhythm s (1997)

Period


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Universidad de Vigo

Peak Time of Functions

WBC

Courtesy of Smolensky MH.

Noon

Midnight

6 PM 6 AM

Calcitonin gene-related peptide

Gastric acid secretion

Peripheral blood flow

(forearm)Diuresis

CholesterolTriglycerides

Insulin

Airway patencyRespiratory rate

Hemoglobin

Atrial natriuretic peptide

Growth hormone

Lymphocytes, TSH

Prolactin

Eosinophils

MelatoninACTH

FSH, LH

Cortisol

Catecholamine surge

Blood pressure/

Heart rate surgeArterial compliance/Vascular resistance

Plasma renin activity

Aldosterone, Angiotensin

Platelet adhesiveness

Blood viscosity

Human Circadian Time Structure


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Universidad de Vigo

CardiovascularOscillators


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Universidad de Vigo

Cardiovascular Oscillators

Mammalian (Rodent) ModelsHeart Muscle

Vascular Wall

Endothelial Cells

Plasminogen Activator Inhibitor 1 (PAI-1)

Human

PAI-1SCN - Changes in Essential Hypertension


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Universidad de Vigo

Diurnal Rhythms in Gene Expression in the

Normal Murine HeartMartino T, et al., J. Mol. Med 2004; 86:256-264

There is a significant and coordinated variation in abroad range of genes of structural & functional

importance over the 24-hour day/night (diurnal) cycle

in the normal adult heart.

STIMULI

CARDIAC

GENES

SCN

CLOCK

Courtesy Dr. SOLE


10/28


Universidad de Vigo

Microarray Technology

**

**

*

GeneSequence

Multipleoligo probes

Perfect Match

Mismatch

5 3

1.28cm

Single stranded,

labeled cRNA target

Image of Hybridized Probe Array

oligonucleotide probes

Hybridized ProbeCell

20m

GeneChipProbe Array

Cour tesy Dr. SOLE


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Universidad de Vigo

DAY REPRESSED

Courtesy Dr. SOLE


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Universidad de Vigo

NIGHT REPRESSED

Court esy Dr. SOLE


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Universidad de Vigo

Substances Activating Circadian Clock Gene

Expression in Organ or Tissue Cultures Include:

Angiotensin II

Butyryl cAMP

Calcium Ionophors

CatecholaminesEndothelin-1

Fibroblast Growth Factor

Forskolin

Glucocorticoids

Retinoic Acid

Tumor Promotors


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Universidad de Vigo

Cardiovascular Chronobiology:

the Rationale

the functional organization of the cardiovascular

system shows specific time courses

a temporal organization is present in the clinicalmanifestations of most cardiovascular diseases

the sensitivity of the cardiovascular system to

both pathological mechanisms and therapeutic

interventions is time-dependent

Courtesy Prof.. PORTALUPPI


15/28


Universidad de Vigo

Pathophysiological Triggers of Chronorisk

for Acute Cardiovascular Events

Courtesy Prof.. PORTALUPPI

HEMODYNAMIC FACTORS

blood pressure & heart ratestroke volume & cardiac outputtotal peripheral resistancescoronary blood flowforearm blood flowvascular tonepulmonary arterial pressurecentral venous pressure

plasma volumeLV end-diastolic pressurerenal flowrenal resistancesglomerular filtration ratetubular reabsorptionurinary flow

NEUROHUMORAL FACTORS

autonomic tonenorepinephrine & epinephrinetirosinedopamineserotoninprorenin & reninangiotensin II & aldosteroneACTH & cortisol

endothelinendogenous opioidsnatriuretic peptide systemcalcitonin gene-related peptideNa & K excretioncreatinin & callicrein excretionprostaglandins (prostacyclin)

HEMATOLOGIC FACTORS

platelet aggregabilityfibrinolisis t-PA/PAIblood coagulabilityblood viscosityserum cholesterol

silent myocardial ischemiaangina pectorisunstable anginacoronary spasmmyocardial infarctionsudden death

stroke

pulmonary thromboembolismectopic beatsventricular tachycardiaatrial flutter & fibrillationparoxysmal supraventr. tachyc.aortic aneurysm rupture

spontaneous aortic dissection

TWIN PEAKS


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Universidad de Vigo

Chronopharmacology= the pharmacological basis for chronotherapeutics

Drug and biological rhythms

i.e. the study of drug toxicity, efficacy and/or kinetics

changes according to the moment of its administration,

taking into account the level of biological rhythms at thismoment

Courtesy Prof .BRUGUEROLLE

Biological rhythms and drugi.e. the study of the influence of drug intake on the

biological rhythms i.e. chronotolerance


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Universidad de Vigo

Distribution

Excretion

Biotransformation

Tissue reservoirs

Locus of Action:

Receptors

Absorption

Pharmacokinetics Pharmacodynamics


S f i bilit i h l


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Universidad de Vigo

Sources of variability in pharmacology

PATHOLOGY

Renalfailure

Hepatic failure

Cardiac failure

Immunodpression

Dnutrition

Obesity

Time

Concentration

Pharmacological variability depending on :

PATIENT

Aged

Children

Male or female

Female:

Menstrual cycle

Pregnancy

Suckling

DRUG: galenic

Immediate release

Sustained release

DRUG:

Conditions of administrationSingle dose

Repeated doses

Constant rate infusion

DRUG:

Route of administrationOral: fasting

Cutaneous: patches



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Universidad de Vigo

Chronopharmacology

DRUGTOXICITY

KINETICS

ACTIVITY

CHRONOPHARMACOKINETICS

CHRONOPHARMACODYNAMICS

CHRONOTOXICOLOGY

Biological Rhythms



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Universidad de Vigo

Chronopharmacokinetics

Time

Concentration

Time

Concentration

Time

Concentration

HOURS06.00 h 16.00 h 02.00 h

Drug

pharmacokinetics

depend on the

moment of its

administration

Cour tesy Prof.BRUGUEROLLE


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Universidad de Vigo

Biological rhythms involvment in kinetics of drugs

BIOLOGIC L RHYTHMS

GI tract

pH,

Digestive motility

PH RM COKINETICS

CHRONOKINETICS

RsorptionOral

ParentralCutaneous

Transmucosal

Activity/rest

Posture

Blood flow

Tissular perfusion

Plasma protein binding

Tissular bindingVolume of Distribution

Liver

Other tissues

Rnal

BiliaryOther ways

MtabolismDistribution Elimination

Hep. Enzym. Act.

Hepatic blood flow

Glomerular

filtration,

urinary pH



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Universidad de Vigo

Chronotherapy

Time-dependent administration

of drugs.

Optimizing desired effects.

Minimizing secondary effects.


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Universidad de Vigo

CHRONOTHERAPY = A MUST

THE PATHOLOGY-RISK IS WELL-KNOWN

THE EFFECT OF THE DRUG CAN BE OBTAINED

ONLY BY A TIME-MODULATED THERAPY

THE THERAPEUTIC WINDOWIS SMALL

WHEN THE KINETICS AND/OR THE DRUG

EFFECTS ARE TIME-DEPENDENT

WHEN THE TREATMENT MUST MIMIC THE

TEMPORAL PATTERN OF A FUNCTION


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Universidad de Vigo

Time Matters

Humans and animals respond differently to the sametreatment given at different times of the day.

Drug testing ignores the time of day. Drugs are usuallytested during a rats sleeping period although usuallyadministered to patients during the daytime.

Clinical trials take no account of changing safety andefficacy profiles across the diurnal cycle. Studies areconducted in the daytime for the convenience of bothscientists and subjects.

Cour tesy Dr. SOLE


25/28


Universidad de Vigo

Time Matters

Diurnal molecular cycling in target

tissues is important to consider in timing

therapy for maximal efficacy with

minimal side effects.

Gene expression in the heart is

dramatically different in the day as

compared to the night.

Cour tesy Dr. SOLE

Obj i f


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Universidad de Vigo

Objectives for

chronopharmacological studies

A chronopharmacological study may be designed:

-As a basis for drug treatment of a chronobiological

disease

-As a part of a possible involvement in an identified

variability of drug response

- For its theoretical aspect

- For drug registration

- For a post-marketing (phase IV) relooking study

CONCLUSIONS


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Universidad de Vigo

Cardiovascular metabolism, growth and

remodeling is dynamic and does not occuruniformly over the day/night cycle.

The risk/benefit ratio of a therapeuticintervention is not uniform across the 24 hour

cycle but occurs in a diurnal fashion

Synchrony between extrinsic and intrinsicdiurnal rhythm is integral to healthy organ growth

and renewal. Biological health is orchestrated.

CONCLUSIONS

Cou rtesy Dr. SOLE


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6 am

GOOD HEALTH DEPENDS ON WELL

ORCHESTRATED BIOLOGY

Members of the Cleveland Orchestra, http://www.cris.com/~jadato/orch1.htm

Metabolism,

Growth and

Renewal,

Heart Disease,

TreatmentNoon

Midnight

Harmony among molecular rhythms within the cell is essential for

overall cellular integrity and function the right stoichiometry at the

right place and time

.

Michael Sole

6 pm

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