Chronotherapy

Question 3

Chronotherapy

Answer 3

• more important when half-life<6hours as drug is not in body for the whole day
• very expensive as trials require placebo at both times, and drug at both times (doubles the trial!)

Question 3

Chronotherapeutics

Answer 3

treatment of an illness or disorder that takes into account the body’s natural rhythms and cycles

Question 4

Chronopharmacokinetics

Answer 4

• xenobiotic uptake
• detoxification
• ADMET

Question 5

Chronopharmacodynamics

Answer 5

circadian rhythms in activity of the target protein

Question 6

Problems with chronotherapeutics

Answer 6

• patient compliance
• increased cost of clinical trials
• measurement of circadian phase

Question 7

The clock of disease

Answer 7

early morning (12-6) = asthma attacks, cognitive impairment, most severe depression, migrains

mid-morning (6-12) = myocardial infarction, angina, sudden cardiac death, stroke

afternoon (12-6) = perforated gastric ulcers

evening (6-12) = chronic pain, gout symptoms most obvious

Question 8

Inflammation

Answer 8

• asthma attacks most severe just after midnight
• circadian clock regulates viral pathogenesis
  1. circadian rhythm of cell intrinsic anti-viral responses
  2. influence of rhythms as virus spreads and amplifies
  3. contribution of host cell rhythms versus immune response rhythms

Question 9

Cancer

Answer 9

• circadian clock is thought to gate the cell cycle
• disruption of circadian clock can disrupt the cell cycle
• hence causes an increased risk of cancer in shift workers

Question 10

Chronotypes

Answer 10

chronotype changes with age:
- children = early chronotype
- teenagers = latest chronotype
- adults = average
- elderly = early chronotype

Question 11

Phase markers

Answer 11

-chronotype differs from person to person

phase markers used to determine chronotype:
- melatonin concentrations (ELISA)
- metabolic timetable
- behavioural monitor
- ingestible telemeric sensor
- Munich chronotype questionnaire

Question 12

Chronotherapeutic drugs

Answer 12

pharmacological treatment of a disorder that takes into account the body’s natural rhythms and cycles

e.g. statins

Question 13

Chronoactive drugs

Answer 13

drugs that affect biological timekeeping

e.g. caffeine

Question 14

Caffeine

Answer 14

• most heavily consumed psychoactive drug
• increases alertness and decreases drowsiness/fatigue
• enhances nightime wakefulness
• decreases depth of sleep

Question 15

Targets of caffeine

Answer 15

1. RyR = alters ER calcium release
2. PDE = inhibits cAMP degradation
3. adenosineR = antagonist or inverse agonist

Question 16

Effect of caffeine on biological clockwork

Answer 16

• acute caffeine delays the clock
• chronic caffeine lengthens the circadian period (shown in mice and human + mice cells)
• caffeine likely affects the clock through cAMP
• caffeine likely works synergistically with IBMX to lengthen the cellular circadian period
• normal dietary caffeine sufficient to antagonise up to 50% inhibitory A1 and facilitatory A2A in the brain

Question 17

Actin and the biological clock

Answer 17

• monomeric : polymeric ratio of actin varies throughout the day
• driven by unknown circadian factor in the blood?
• actin rhythms occur cell autonomously

Question 18

Actin and wound healing

Answer 18

• Western blots shown a change in actin levels in cultured fibroblasts throughout the day
• this affects wound healing
  1. haemostasis = blood clot
  2. inflammatory = scab
  3. proliferative
  4. remodelling
• speed and onset of wound healing depending on the time of day
• at some times, fibroblasts are not prepared to move so wound healing takes longer to begin
• actin rhythms require clock gene expression cycles - not detectable in CRY1/2 mutant cells