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HIDETO SHINNO
Traditional Medicine-2015Birmingham, UK
August 03 – 05, 2015
Traditional Traditional
MedicineMedicine
20152015
Herbal Medicine for Sleep Disturbances in the Elderly
Hideto SHINNOKagawa University School of Medicine
Japan
The 3rd International Conference and Exhibition onTraditional & Alternative MedicineAugust 3, 2015 Birmingham, UK
Sleep Disturbances in the Elderly
1. Characteristics of sleep in the elderly
2. Treatment of sleep disturbances
in the elderly
Herbal prescription
for sleep disturbances
Sleep Disturbances in the Elderly
1. Characteristics of sleep in the elderly
2. Treatment of sleep disturbances
in the elderly
Herbal prescription
for sleep disturbances
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
non-REM sleep
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
A prolonged sleep latency
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
Decrease in slow wave sleep (stages III +IV)
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
frequent arousals
PolysomnographySubjects in the Elderly
WREM
IIIIIIIV
sleep stages
Decrease in REM sleep
Sleep in the ElderlyPolysomnography
A shortened total sleep timeA shortened total sleep time A shortened REM sleep timeA shortened REM sleep time
Relatively increased stage IRelatively increased stage I A decrease in slow wave sleep A decrease in slow wave sleep
Increase in PLMsIncrease in PLMs
Periodic limb movements during sleep
Increase in apnea-
hypopneaindex
Increase in apnea-
hypopneaindex
Sleep fragmentation
(frequent arousals)
Sleep fragmentation
(frequent arousals)
IncreasedWake time
after sleep onset
IncreasedWake time
after sleep onset
Periodic Limb Movement during Sleep (PLMs)
Repetitive, stereotyped movements
of the lower extremities in sleep
Rhythmic extensions of the big toe
and dorsiflexions of the ankle
Periodic Limb Movement during Sleep (PLMs)
Repetitive, stereotyped movements
of the lower extremities in sleep
Rhythmic extensions of the big toe
and dorsiflexions of the ankle
Followed by Accelerated heart
rates
Followed by Accelerated heart
rates
Periodic Limb Movement during Sleep (PLMs)
Repetitive, stereotyped movements
of the lower extremities in sleep
Rhythmic extensions of the big toe
and dorsiflexions of the ankle
frequent arousals
sleep disruption
Increase in PLMs
Followed by Accelerated heart
rates
Followed by Accelerated heart
rates
Periodic Limb Movement during Sleep (PLMs)
Repetitive, stereotyped movements
of the lower extremities in sleep
Rhythmic extensions of the big toe
and dorsiflexions of the ankle
frequent arousals
sleep disruption
Increase in PLMs
PLM DisorderPLMs > 15 / hourAmerican Academy of Sleep Medicine (2005)
Periodic Limb Movement during Sleep (PLMs)
Repetitive, stereotyped movements
of the lower extremities in sleep
Rhythmic extensions of the big toe
and dorsiflexions of the ankle
frequent arousals
sleep disruption
Increase in PLMs
After awakenings
PLMs disappears
Periodic Limb Movement during Sleep (PLMs)
Repetitive, stereotyped movements
of the lower extremities in sleep
Rhythmic extensions of the big toe
and dorsiflexions of the ankle
frequent arousals
sleep disruption
Increase in PLMs
After awakenings
PLMs disappears
Patients are usually unaware of PLMs.
Patients are usually unaware of PLMs.
Sleep in the ElderlyPolysomnography
A shortened total sleep timeA shortened total sleep time A shortened REM sleep timeA shortened REM sleep time
Relatively increased stage IRelatively increased stage I A decrease in slow wave sleep A decrease in slow wave sleep
Increase in PLMsIncrease in PLMs
Periodic limb movements during sleep
Increase in apnea-
hypopneaindex
Increase in apnea-
hypopneaindex
Sleep fragmentation
(frequent arousals)
Sleep fragmentation
(frequent arousals)
IncreasedWake time
after sleep onset
IncreasedWake time
after sleep onset
Sleep Disturbances in the Elderly
1. Characteristics of sleep in the elderly
2.Treatment of sleep disturbances
in the elderly
Herbal prescription
for sleep disturbances
Prescriptions for sleep disturbances
Prescriptions for sleep disturbances
Benzodiazepines
Prescriptions for sleep disturbances
Benzodiazepines
hangover effects
prolongation of the hypnotic effect
Prescriptions for sleep disturbances
Benzodiazepines
hangover effects
prolongation of the hypnotic effect
amnesia, delirium
Prescriptions for sleep disturbances
Benzodiazepines
hangover effects
prolongation of the hypnotic effect
amnesia, delirium
Contraindications
sleep apnea syndrome
Prescriptions for sleep disturbances
Benzodiazepines
hangover effects
prolongation of the hypnotic effect
amnesia, delirium
Contraindications
sleep apnea syndrome
Insufficient efficacy
periodic limb movement (PLM)-assocoated arousals
Prescriptions for PLM
Clonazepam
Dopaminergic agentsL-dopaHening W, et al. (1999) Sleep 22: 970-99Brodeur C, et al. (1988) Neurolgy 38: 1845-8
PramipexoleJama L, et al. (2009) Sleep Med 10: 630-6Manconi M, et al. (2007) Sleep Med 8: 491-7
Saletu M, et al (2001) Eur Neuropsychopharmacol 11: 153-61Milter MM, et al. (1986) Sleep 9: 385-92Boghen D, et al (1986) Can J Neurol Sci 13: 245-7
GABA
dopamine
Sleep Disturbances in the Elderly
The effect of Herbal prescription
TJ-54 on sleep disturbances
Yokukansan (YKS)Yokukansan (YKS)The herbal prescription
Yokukansan, TJ-54Yi-Gan SanPulvis deressionis efficientiae
Introduction
Yokukansan (YKS)
The herbal prescription
Introduction
Yokukansan (YKS)
The herbal prescription
YKS was originally developed as a remedy for restlessness and agitation in children.
Introduction
Yokukansan (YKS)
The herbal prescription
YKS was originally developed as a remedy for restlessness and agitation in children.
In Japan, YKS has been approved for neurosis, insomnia, and night time crying in children.
Introduction
Yokukansan (YKS)
The herbal prescription
YKS was originally developed as a remedy for restlessness and agitation in children.
In Japan, YKS has been approved for neurosis, insomnia, and night time crying in children.
Recently YKS is prescribed for psychiatric symptoms in dementia.
Atractylodis
Lanceae Rhizoma
Glycyrrhizae Radix
AngelicaeRadi
x
Cnidii Rhizom
a
Bupleuri
Radix
Hoelen
Uncarie Uncis Cum
Ramulus
The Ingredients of YKS
The Ingredients of YKS7 herbs
Yokukansan (YKS)Yokukansan (YKS)Extract Granules for Ethical Use
The effect of YKS on sleep disturbancesin patients with Dementia
Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.
Polysomnography
YKS administration (7.5 g/day)
YKS treatment days (week)mean age: 81±7 years oldAlzheimer’s disease: 4 casesDementia with Lewy bodies: 4 cases
The effect of YKS on sleep disturbances
Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.
time (min)
The effect of YKS on sleep disturbances
Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.Significant increase
in Total Sleep Timeand WASO
Significant increase in Total Sleep Time
and WASO
time (min)WASO; wake time after sleep onset
The effect of YKS on sleep disturbances
Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.Significant
increase in Stage II Sleep
Significant increase in
Stage II Sleep
time (min)
Number of awakenings at night
After YKS treatment, number of awakenings significantly decreased.
Shinno H, et al. (2008) Prog Neuro-Psychopharm Biol Psychiat
No. ofarousals
*P<0.0 5
*
The effect of YKS on PLM during sleep
Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.
PLMs index(No. / hour)
PLMs index=No. of PLMs / sleep time (hour)
The effect of YKS on sleep disturbances
Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.
PLMs index(No. / hour)
** **p<0.01
YKS reduced PLMs.YKS reduced PLMs.
Pittsburgh Sleep Quality Index (PSQI)
YKS treatment improved subjective sleep quality.
developed by Buysse et al. (1989)
PSQI score
Shinno H, et al. (2008) Prog Neuro-Psychopharm Biol Psychiat
baseline YKS-treated
*
*P<0.05
Effect of YKS on Insomnia in the (non-demented) Elderly
Effect of YKS on Insomnia in the (non-demented) Elderly
Subjects: 10 patients with neurotic disorders 4 males and 6 femalesmean age 73.3±4.4 years old
Methods:Polysomnography was carried out
at adaptation night, baselineafter treated with YKS for 4 weeks
Sleep architectures and PLMs index were compared.
Adaptation night
-1d
baseline After treatmentYKS5g/d (evening and bedtime)For 4 weeks
Effect of YKS on Insomnia in the (non-demented) Elderly
Time (min)
Effect of YKS on Insomnia in the (non-demented) Elderly
Time (min)Improved Daytime
sleepiness
Improved Daytime
sleepiness
NOT affectedApnea-IndexNOT affectedApnea-Index
Effect of YKS on Insomnia in the (non-demented) Elderly
**
**p<0.01
Effect of YKS onRestless Legs Syndrome (RLS)
Restless legs syndrome (RLS)Four essential criteria
I) An urge to move the legsOften associated with discomfort sensations
I) An urge to move the legsOften associated with discomfort sensations
The International RLS Study Group (2005)
Paraesthesia/ dysesthesia
II) Begin or worsenDuring periods of REST or Inactivity
II) Begin or worsenDuring periods of REST or Inactivity
Lying down or sitting
III) Be partially or totally relieved by movement
III) Be partially or totally relieved by movement
IV) Occur predominantly in the evening or night
IV) Occur predominantly in the evening or night
Walking or stretching Few occur in the daytime
Restless legs syndrome (RLS)Four essential criteria
I) An urge to move the legsOften associated with discomfort sensations
I) An urge to move the legsOften associated with discomfort sensations
The International RLS Study Group (2005)
Paraesthesia/ dysesthesia
II) Begin or worsenDuring periods of REST or Inactivity
II) Begin or worsenDuring periods of REST or Inactivity
Lying down or sitting
III) Be partially or totally relieved by movement
III) Be partially or totally relieved by movement
IV) Occur predominantly in the evening or night
IV) Occur predominantly in the evening or night
Walking or stretching Few occur in the daytime
Sleep disturbancesSleep disturbances
Pathophysiology of Restless legs syndrome (RLS)
Iron deficiency Renal failureParkinson’s diseaseneuropathy
HypothalamusA11 dopaminergic
system
HypothalamusA11 dopaminergic
systemRLSRLS
DA decrease
Treatment of Restless legs syndrome (RLS)
RLSRLSDopaminergic agents
PramipexoleRopiniroleRotigotine
improvementimprovement
Adverse EffectsAdverse Effects
Nausea(visual) hallucinationsAugmentationMorning rebound
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
RLS severity
IRLS score
Side effectsSide effects
YKS 5g/dayYKS 5g/day
Previous treatments Smaller doses of PPX
0 2 4 6
YKS treatment days (weeks)
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
RLS severity
IRLS score
Side effectsSide effects
YKS 5g/dayYKS 5g/day
Previous treatments Smaller doses of PPX
0 2 4 6
YKS treatment days (weeks)
Severe RLS
Extra-severe:IRLS>31
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
RLS severity
IRLS score
Side effectsSide effects
YKS 5g/dayYKS 5g/day
Previous treatments Smaller doses of PPX
0 2 4 6
YKS treatment days (weeks)
moderate RLS
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
RLS severity
IRLS score
Side effectsSide effects
YKS 5g/dayYKS 5g/day
Previous treatments Smaller doses of PPX
0 2 4 6
YKS treatment days (weeks)
mild RLS
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
RLS severity
IRLS score
Side effectsSide effects
Previous treatments
0 2 4 6
YKS treatment days (weeks)
Before visiting to my Dept.Before visiting to my Dept.
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
RLS severity
IRLS score
Side effectsSide effects
YKS 5g/dayYKS 5g/day
Previous treatments Smaller doses of PPX
0 2 4 6
YKS treatment days (weeks)
YKS for patients with RLS who had complained of side effect against previous treatment
Self-report total sleep time
YKS treatment days (weeks)
Self-report sleep latency time
YKS for patients with RLS who had complained of side effect against previous treatment
Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-
EpworthSleepinessScale score Side effectsSide effects
YKS 5g/dayYKS 5g/day
Previous treatments Smaller doses of PPX
0 2 4 6
Daytime somnolence improvedDaytime somnolence improved
YKS treatment days (weeks)
YKS may be effective for sleep disturbances in the elderly.
What pharmacological properties are beneficial ?
In the elderly, functions of dopamine (DA) and serotonin (5-HT)
are declined.
YKS increases 5-HT and DA levels in the aged rats
Mizoguchi K, et al. (2010) J Ethnopharmacol 127: 70-76.
Effect of YKS on 5-HT and DA systemAt prefrontal cortex in aged and young rats
YKS increases 5-HT and DA levels in the aged rats
Mizoguchi K, et al. (2010) J Ethnopharmacol 127: 70-76.
In aged rats, Decreases in
•Basal 5-HT and DA levels•KCl-induced 5-HT release and DA release
Effect of YKS on 5-HT and DA systemAt prefrontal cortex in aged and young rats
YKS increases 5-HT and DA levels in the aged rats
Mizoguchi K, et al. (2010) J Ethnopharmacol 127: 70-76.
YKS administarationYKS administaration
In aged rats, Decreases in
•Basal 5-HT and DA levels•KCl-induced 5-HT release and DA release
Increased5-HT and DA
releases
Increased5-HT and DA
releases
Effect of YKS on 5-HT and DA systemAt prefrontal cortex in aged and young rats
The Effect of YKS
on the on the serotonin (5-HT) systemserotonin (5-HT) system on the on the serotonin (5-HT) systemserotonin (5-HT) system
Repeated administration of YKS modulatesan altered function of 5-HT2A receptors.
Egashira,N . et al. (2008) Prog Neuro-Psychopharmacol Biol Psychiatry 32: 1516-20 .
Repeated administration of YKS inhibits DOI-induced head-twitch response
100 300 0
YKS (p.o.)
DOI 5mg/kg (i.p.)
20
15
10
5
0
hea
d-tw
itche
s /
5min
(repeated) 13days YKS +
YKS (p.o.)DOI (i.p.) head-twitch
DOI : 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
mg/kg
*
DOI induces head-twitch via 5-HT2A receptor.
Egashira,N . et al. (2008) Prog Neuro-Psychopharmacol Biol Psychiatry 32: 1516-20 .
Repeated administration of YKS inhibits DOI-induced head-twitch response
100 300 0
YKS (p.o.)
DOI 5mg/kg (i.p.)
20
15
10
5
0
hea
d-tw
itche
s /
5min
(repeated) 13days YKS +
YKS (p.o.)DOI (i.p.) head-twitch
DOI : 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane
mg/kg
*
DOI induces head-twitch via 5-HT2A receptor.
Egashira,N . et al. (2008) Prog Neuro-Psychopharmacol Biol Psychiatry 32: 1516-20 .
Repeated administration of YKS inhibits DOI-induced head-twitch response
100 300 0
YKS (p.o.)
DOI 5mg/kg (i.p.)
20
15
10
5
0
hea
d-tw
itche
s /
5min
(repeated) 13days YKS +
YKS (p.o.)DOI (i.p.) head-twitch
mg/kg
*
Over-activated5-HT2A receptors
Over-activated5-HT2A receptors
restoredrestoredYKS
The Effect of YKS
on the on the GABA systemGABA system
γ-aminobutyric acid
The effect of YKS on the GABA system
Aim: To elucidate the mechanism of the anxiolytic-like effects in mice
YKS increased the number of head-dipping behavior, an indicator of anxiolytic effect.
Pretreatment with Flumazenil, GABA-BZP receptor antagonist
Behavioral study with the hole-board test
The effect of YKS was inhibited.
Kamei J (2009) Prog Neuropsychopharmacol Biol Psychiatry 33: 1431-7
The effect of YKS on the GABA system
Aim: To elucidate the mechanism of the anxiolytic-like effects in mice
YKS increased the number of head-dipping behavior, an indicator of anxiolytic effect.
Pretreatment with Flumazenil, GABA-BZP receptor antagonist
Behavioral study with the hole-board test
The effect of YKS was inhibited.
Kamei J (2009) Prog Neuropsychopharmacol Biol Psychiatry 33: 1431-7
The effect of YKS on the GABA system
Aim: To elucidate the mechanism of the anxiolytic-like effects in mice
YKS increased the number of head-dipping behavior, an indicator of anxiolytic effect.
Pretreatment with Flumazenil, GABA-BZP receptor antagonist
Behavioral study with the hole-board test
The effect of YKS was inhibited.
Kamei J (2009) Prog Neuropsychopharmacol Biol Psychiatry 33: 1431-7
The effect of YKS on Sleep DisturbancesHypothesis on the mechanism
The effect of YKS on Sleep DisturbancesHypothesis on the mechanism
Improve Sleep Continuity(Decrease in awakenings at night )
Improve Sleep Continuity(Decrease in awakenings at night )
Restore ofSleep architecture
Restore ofSleep architecture
Decrease inPLMs
Decrease inPLMs
Increase intotal sleep time
Increase intotal sleep time
The effect of YKS on Sleep DisturbancesHypothesis on the mechanism
DopamineDopamine
YKS
Improve Sleep Continuity(Decrease in awakenings at night )
Improve Sleep Continuity(Decrease in awakenings at night )
Restore ofSleep architecture
Restore ofSleep architecture
Decrease inPLMs
Decrease inPLMs
Increase intotal sleep time
Increase intotal sleep time
The effect of YKS on Sleep DisturbancesHypothesis on the mechanism
DopamineDopamine
YKS
Improve Sleep Continuity(Decrease in awakenings at night )
Improve Sleep Continuity(Decrease in awakenings at night )
GABAGABA
Restore ofSleep architecture
Restore ofSleep architecture
Decrease inPLMs
Decrease inPLMs
Increase intotal sleep time
Increase intotal sleep time
The effect of YKS on Sleep DisturbancesHypothesis on the mechanism
DopamineDopamine5-HT5-HT
YKS
Improve Sleep Continuity(Decrease in awakenings at night )
Improve Sleep Continuity(Decrease in awakenings at night )
GABAGABA
Restore ofSleep architecture
Restore ofSleep architecture
Decrease inPLMs
Decrease inPLMs
Increase intotal sleep time
Increase intotal sleep time
Atractylodis
Lanceae Rhizoma
Glycyrrhizae Radix
AngelicaeRadi
x
Cnidii Rhizom
a
Bupleuri
Radix
Hoelen
Uncarie Uncis Cum
Ramulus
The Ingredients of YKS The Ingredients of YKS
Atractylodis
Lanceae Rhizoma
Glycyrrhizae Radix
AngelicaeRadi
x
Cnidii Rhizom
a
Bupleuri
Radix
Hoelen
Uncarie Uncis Cum
Ramulus
The Ingredients of YKS The Ingredients of YKS
5-HTGABA5-HT
GABA
5-HTGABA5-HT
GABA
dopamineGABA
dopamineGABA
YKS
Summary
★ effective for sleep disturbances in the elderly
★ few adverse events
extrapyramidal signs
hang-over effects
symptoms associated with anti-cholinergic effect
dopaminedopamine serotoninserotonin GABAGABA
Caution: lowering serum K+Caution: lowering serum K+
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