CIRCADIAN RHYTHM

Presented to: Sir Sherjeel Adnan Circadian rhythm Chronotherapeutics Enzymatic cleavage Hydrolytic cleavage

Presented by: Maryam Shabbir Advanced Pharmaceutics M.phil Pharmaceutics The University of Lahore

INDEX Page number

Circadian rhythm Circadian rhythm cycle Factors effecting circadian rhythm Chronotherapeutics COER-24 verapamil 2 3 4 5 5

Enzymatic cleavage Hydrolytic cleavage

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References

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CIRCADIAN RHYTHM
Circadian rhythm
Physical Mental Behavioral changes
1

That follows a 24-hour cycle, responding primarily to LIGHT and DARKNESS in an organisms environment. SCN controls the production of melatonin, a hormone that makes you sleepy. It is located just above the optic nerves, which relay information from the eye to the brain. The SCN receives information from incoming light. When there is less light- like at night- the SCN tells the brain to make more melatonin to make person drowsy. Circadian rhythm can change Sleep-wake cycle Hormonal release Body temperature Other important bodily function

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GRAPH I

GRAPH Page 4

II

Factors effecting circadian rhythm

GRAPH III

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Chronotherapeutics

Chronotherapeutics is a delivery of a medication in concentrations that vary according to physiological need at different times during the dosage period. The first chronotherapeutic agent for hypertension and angina pectoris, controlled onset, extended release (COER-24) verapamil, has recently been developed and registered in the US, Brazil, Canada and Mexico. The theoretical advantage of this formulation is that delivery of the active drug, verapamil, has been tailored to the typical circadian rhythm of blood pressure and heart rate in patients with hypertension and angina to better cover the early morning hours when cardiovascular need appears to be the greatest.

COER-24 Verapamil

In two-double-blind, randomized, placebo controlled studies of 382 total patients with mild and moderate hypertension; clinically significant 24-hour blood pressure control was determined and demonstrated with one-daily dose, evening doses of COVERA-HS (180mg/day to 540 mg/day) with peak effects between 6:00 a.m and noon. Advanced COER-24 DDS consists of two stages It provides for a 4-5 hour delay in drug release after bedtime administration. At approximately 3 hours before awakening, drug release occurs so that peak level of medication coincides with wakening and the first hour of activity. The extended release of drug in the GIT provides 24-hour control of blood pressure and symptoms of angina pectoris.

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Enzymatic Cleavage
Several anticancer prodrugs have been designed for selective activation in malignant tissue by a specific enzyme, which is targeted or secreted near tumor cells. The release of the free drug bt a specific enzyme only takes upon cleavage of prodrug protecting group. Rate limiting steps for the release of free drug are: i. ii. iii. Total amount of targeted drug Rate Concentration of the specific enzyme

Incorporation of drug molecules as the tail units and an enzyme substrate as the trigger can generate a multi-prodrug unit that will be activated with a single enzymatic cleavage. Example: Bioactivation Of Self-Immolative Dendrimer Prodrug: Dendrimer: Dendron means tree Meros means part These are unique and optimum nano-carrier in medical application such as Drug delivery Tumor therapy Diagnosis etc

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Self-Immolative Dendrimer has incorporated drug molecule as the tail and an enzyme substrate as the trigger which can generate a multi-prodrug unit that will be activated with a single enzymatic cleavage.

Dendritic prodrugs with doxorubicin and camptothecin as tail units and a retro-aldol retro-Michael focal trigger, which can be cleaved by catalytic antibody 38C2.

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Hydrolytic cleavage
Hydrolysis is a chemical reaction during which molecule of water is split into H and OHin a process of chemical mechanism.

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References: 1. Circadian rhythm- Keeping time Progress from the National Institute of General Medical Sciences Content created: July 2008 Review date: august 19, 2011 2. Chronotherapeutics for CV disease Author: Anwar Y.A., White W.B. Drugs, vol. 55, Number 5, May 98 p. 631-643 Publisher: Adis International 3. Searle, COVERA-HS Verapamil HCL US FDA approved Feb 27, 19995 4. Bioactivation Of Self-Immolative Dendrimer Prodrug by catalytic antibody 38C2 Marina SHamis, Holger N. Code and Doron Shabat J.Am.Chem.Society Vol. 126, number 6, 2004 5. Lippincotts illustrated review Pharmacology 3rd edition By: Richard D. Howland. Mary J. Mycek Pg. 498

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