Chrono-neuropharmacology 3

Question 1

Environmental/behavioural targeting of the clock: Bright Light Therapy (BLT)

Answer 1

Typically involves high intensity blue light exposure early in the day
Targets: affective disorders, insomnia, AD, jet lag
Benefits: improved mood; enhanced sleep efficiency; increased melatonin level gradient

Question 2

Remission rate in mild-severe depression achieved by light treatment

Answer 2

40-67%

Question 3

Environmental/behavioural targeting of the clock: Melatonin

Answer 3

Targets: blind and elderly, depression, AD, sleep disturbance, jet lag
Agomelatine: MT1-, MT2- (agonist) and 5HT2C-Rs (antagonist); efficacious in animal models of depression; resynchronisation in animal models of jet lag, blindness, delayed-phase syndrome

Question 4

Environmental/behavioural targeting of the clock: CBT

Answer 4

Originally developed for primary insomnia but now use for comorbidities
Behavioural components (e.g. relaxation techniques, sleep restriction)
Cognitive components (correcting unhelpful attitudes about sleep)
Educational component (sleep hygiene)
Effective in reducing the severity of depressive symptoms and suicidal ideation

Question 5

Basis of CBT for sleep

Answer 5

Gradual increase of sleep window

Question 6

Environmental/behavioural targeting of the clock:

Entrainment therapy in Alzheimer’s Disease

Answer 6

AIM: increasing patients’ levels of physical activity and social relations, and decreasing the time spent asleep during the day
Light therapy: Increases night-time sleep; Higher daytime activity; Lower daytime sleep
Melatonin: Increases sleep time; decreases nocturnal activity; no change in daytime sleep

Question 7

CK1 inhibitors

Answer 7

CK1 inhibitors (e.g. Pfizer compound); Control period, entrainment; Chronic dosing normalized manic behaviour in ClockΔ19 mice; Rescue of disrupted circadian behaviours; CK1δ inhibition can be used to lengthen period of circadian rhythms; CK1δ inhibition lengthens period of locomotor activity in vivo

Question 8

Psychostimulants: Caffeine

Answer 8

Antagonist at Adenosine receptor

Question 9

Psychostimulants: Nicotine

Answer 9

Improved cognitive performance (alertness, hand-eye
coordination, concentration, reaction times, short-term
memory)
Reduces duration and quality of sleep
Mimics action of acetylcholine

Question 10

Psychostimulants: Amphetamines

Answer 10

Can directly entrain rhythmic behaviour and alter circadian clock function (rebound effects and many side effects)

Question 11

Chronotherapeutics

Answer 11

Refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease

Question 12

Aims of chronotherapeutics

Answer 12

Optimise therapeutic outcomes; minimise side effects; maximise drug side effects; match circadian variation of disease

Question 13

Circadian variation in toxicity

Answer 13

Ouabain; derived from plants, arrow poison in cardiac glycoside; use medically for hypotension and heart arrhythmias
In mice, 74% die if given during the day, 80% if given during the night

Question 14

Circadian variation in drug metabolism (absorption)

Answer 14

Absorption rates vary with 24hr rhythms in gastric acid secretion and pH, motility, gastric emptying time, GI blood flow (lipophilic absorbed better in morning)

Question 15

Circadian variation in drug metabolism (metabolism and elimination)

Answer 15

Drug metabolism and elimination (liver) will vary with liver enzyme activity, hepatic blood flow, glomerular filtration, renal blood flow, urinary pH, tubular reabsorption

Question 16

Circadian variation in drug metabolism (drug availability)

Answer 16

Drug availability can vary with rhythms in carrier proteins and efflux proteins
Blood carrier protein for cortisol, transcortin, exhibit rhythm thus rhythm in free (effective) hormone concentration

Question 17

Circadian variation in passage through the BBB

Answer 17

Therapeutic drugs targeting the CNS should be given at the optimal circadian times for BBB entry
(Decreased xenobiotic efflux at night- drug accumulation)
Anti-seizure drug phenytoin is more effective when administered at night (in drosophila)

Question 18

Circadian variation in disease

Answer 18

diagram

Question 19

Circadian variation in arthritis

Answer 19

Circadian variation in symptoms and in disease markers

Delayed release prednisone improves morning joint stiffness and decreases circulating IL6

Question 20

Circadian variation in statin efficacy

Answer 20

HMG-CoA reductase strongly circadian with peaks at night thus statins most effective when taken before bed

Question 21

Chronotherapy in chemotherapy

Answer 21

Tolerance major issue in chemotherapy
Cell cycle is timed thus sensitivity to cytotoxic agents is too; 30-40% of anti-cancer drugs show circadian variation in toxicity

Question 22

Circadian variation in 5-Fluorouracil

Answer 22

Anti-metabolite that substitutes for uracil (inhibits pyrimidine synthesis;) Its target enzyme is thymidilate synthase (TS)
5-FU disrupts DNA synthesis = peak toxicity at S-phase of cell cycle; 10-20 min half-life in plasma (typically given by infusion);
Chronomodulatory vs fixed rate: less hospitalisation, reduced oral stomatitis, peripheral sensory neuropathy, better at reducing tumour to operable size; increased survival