Melatonin Melatonin

Clocking in! in!

Homeostasis

Circadian rhythm

Temperature

Growth hormone

Cortisone

Prolectine

Urinary K+

Chrono-biology

Asthma 5am

Stroke 5-7amAllergic rhynitis 6am

Stable angina 10amunstable angina 1-3am

heart attack 6-8am

Hypertension 10am-2pm

Rheumatoid arthritis 6-8am

Osteoarthritis 4-6pm

Ulcer disease 4am5pmMigraine 4-6pm

Chrono-therapeutics

Homeopathic Chrono Pharmacology

Hamster Test

Biological

Suprachiasmatic nucleus

Eye

SCN SCG

PinealSleep Wakecycle

Temperaturerhythm

Melatonin

Circadian rhythm physiology

“Chronobiotics are substance which can therapeutically

adjust the timing of the circadian rhythms”

2.00 P.M. 8.00 P.M. 3.00 A.M 7.00 A.M.

Time Of Day

Melatonin secretion

Melatonin secretion at night

Melatonin and Sleep

Normal circadian rhythm

Winter circadian rhythm

Summer circadian rhythm

0 10 20 30 40 50 60 70

Sleep Duration

Melatonin Secretion

Age in Year

Melatonin levels sleep and age

Melatonin Metabolism

Tryptophan 5Hydroxytryptophan 5Hydroxytryptamine

N Acetylserotonin

Melatonin

6-hydroxymelatonin SO4 (liver)

N-acetyl-5methoxy-kynurenamine

Melatonin function?

• Regulate circadian rhythm

• Control other hormone through pituitary?

• Immunomodulator

• Oncostatic

• Free radical scavenger

Disorders of melatonin

• Hypomelatonism

• Hypermelatonism

• Dysmelatonism

Hypomelatonism

• Old age

• Pineal tumors

• Psychiatric disorders: depression, schizophrenia

• Mentally retarded and autistic

• Alcohlism

• Autonomopathy

• Klinefelder's and Turner's syndrome

• Neoplasm: liver, kidney, upper respiratory tract, breast, skin and prostate

• Some cases of coronary heart disease.

Drug induced hypomelanonism

• Betablockers: Metaprolol->propranolol->Atenolol

• Alpha 2 blocker: Clonidine

• Naloxone• NSAID ibuprofen

• Alcohol, tobacco, caffeine

• Benzodiazepine

Hypermelatonism

Seasonal affective disorder (SAD)

• Extreme fatigue and lack of energy• Increased need for sleep• Carbohydrate cravings• Weight gain• Reduced work productivity• Withdrawal from social contacts

• Exposure to light improve

Dysmelatonism

Circadian rhythm SyndromeCircadian rhythm Syndrome

• Blind

• Jet lag

• Night shift workers ( Industrial jet lag)

• Delayed sleep phase syndrome

Clinical features of CRS

• Disruption of sleep

• Decreased attention span– Decreased work

efficiency

– Work- and non-work related accidents

• Irritability• Headaches

• Fatigue

• Substance abuse

• Depression

• Reduced Immunity

• Cardiovascular and

• Gastrointestinal disorders

Westward time zone flight

Eastward time zone flight

Delayed sleep phase syndrome

Melatonin in insomnia

• Circadian rhythm disturbance most

effective

• Insomnia with psychological diseases

slight improvement

• Insomnia with structural disease no

response

Advantage of melatonin

• Nontoxic

• No tolerance

• No hangover

• No suppression of REM sleep

Administration

• 0.1mg to 200mg

• As little as 0.3 - 0.5 mg is usually effective as a sleep aid.

• Regular low dosage use for sleep should be limited to one month.

• Start slowly and increase till achieve normal sleep and no early morning drowsiness

Pharmacokinetics

• Absorption: 60-150min

• Elimination half life: 45-60min

• Metabolism in liver and brain

Melatonin in various age groups

• Age Group Teens - 20's: Should take Melatonin only occasionally for insomnia.

• Age Group 30 - 50: Can use it more frequently.

• Age Group over 60: Daily use is recommended.

Caution• Psychotics

• Manic depression

• Immune system disorders: autoimmune and malignant disorders

• Diabetes and endocrine diseases

• Hypertension and cardiovascular disease

• Children and young reduces sperm count

• Pregnancy and breast feeding

Adverse reaction(large dose)

• Morning drowsiness • Vivid dreams ->Nightmares, • Confusion • Nausea • Mild depression• Headache • Reduced sex drive• Vasoconstriction in Animal studies.

Safety profile

• LD-50 not known

• Hypothermia

• There is little evidence to support

the safety of long-term use.

Drug interaction

• Not well known

• Anti depressant may increase melatonin

level

• Estrogen reduces melatonin level and

• Melatonin reduces estrogen level

Natural way to increase melatonin

• Early to bed and early to rise ………..

• Food: Oats, sweet corn, rice, barley, tomatoes and bananas

• Vitamin B3, B6 (dried apricots, barley, whole wheat, tuna and turkey, rice, bananas, lentils, shrimp and carrots)

Natural way to increase Melatonin

• Meditate regularly

• Avoid too much caffeine and

alcohol, and stop smoking.

• Anti-oxidant supplements keeps

pineal gland healthy

1.Extend life........…

2.Prevent pregnancy

3.Protect from free -

radical damage.…

4.Boost the immune

system.....…

5.Prevent cancer......

Melatonin Claims!

Melatonin extend life

• Melatonin secretion reduces with aging in

80% population

• Cross transplantation of pineal gland

• Aging is due to oxidative injury to cell wall

and DNA

• Melatonin is a strong antioxidant

Melatonin and Reproduction

• Melatonin controls growth hormone level

• Precocious puberty have low melatonin while delayed puberty have high

• Higher levels of melatonin are associated with male infertility and with the cessation of menstruation in women who exercise heavily or suffer badly from stress

Immunomodulation

• Melatonin activated monocytes... and enhance

their ability to destroy nonself cells.

• Melatonin influenced the release of IL-1 proteins

that control aspects of blood-cell production and

the immune response.

• Melatonin could restore the function of T-helper

cells and IL2 in immunocompromised mice.

Melatonin as antioxidant

• In vitro melatonin is more effective than glutathione in scavenging the highly toxic (OH) radical

• More efficient than vitamin E in neutralizing the peroxyl radical.

• It also stimulates the main antioxidant enzyme of the brain, glutathione peroxidase.

• In vivo melatonin is a potent antioxidant

Melatonin in Cataract

•Glutathione depletion by Glutathione

synthesis inhibitor buthione sulfoxemine

(BSO) produces cataract in young mice

•Melatonin administration prevent cataract

formation by antioxidant effect

Melatonin in Cancer

• Increased incidence of ovarian and breast cancer after pinealectomy

• Melatonin suppresses growth of prostate and breast carcinoma

• Anti cancer effect may be due to anti Prolectine, estrogen and growth hormone effect

• Melatonin changes expression of cell membrane estrogen receptor

• Melatonin may enhances anti tumor activity of IL2 by inhibiting tumor growth factor production in endometrial carcinoma

More melatonin relationship

• Fibromyalgia: reduced melatonin • Epilepsy: high dose may be effective• Trypanosomiasis: Circadian rhythm

disturbance• Pain: to induce painless sleep• Tinnitus: to induce sleep• Hypercholesteremia: reduces LDL receptor• Antistress

This billion year old

chronobiotic molecule

will change our approach

to medicine for the next

millenium

Thank you