Traditional Medicine-2015
Birmingham, UK
August 03 – 05, 2015
Zhang-Jin Zhang
3rd International Conference and Exhibition on
Traditional & Alternative Medicine
August 03-05, 2015 Birmingham, UK
In Association with
Presented By
Name: Zhang-Jin Zhang
Country: The University of Hong Kong, Hong Kong
Peony-Glycyrrhiza decoction, an herbal
preparation against antipsychoticinduced hyperprolactinemia:
from bedside to bench (“B2B”)
Zhang-Jin Zhang, Professor
The University of Hong Kong
Traditional Medicine 2015, Birmingham
Psychotropic potential of
herbal medicine



Develop new drugs from
herbal medicines.
Enhance the clinical efficacy.
Reduce adverse side effects
caused by conventional drugs.
Zhang, 2004.
Peony-Glycyrrhiza Decoction (PGD)

A traditional Chinese herbal
formula (芍药甘草汤).

Paeonia (peony) and glycyrrhiza
(liquorice) radices in a ratio of 1:1.

Initially used to muscle spasm in
TCM practice.

Potential to reduce hyperPRL.
HPLC profile of PGD
Wang et al., 2012.
A pilot trial of PGD to treat
HyperPRL (2008)
Inclusion criteria

Schizophrenic females aged 18-45 yrs;

Current conditions were stable;

Under antipsychotic maintenance
treatment for at least 6 months;

Had hyperPRL-related symptoms:
oligomenorrhoea or amenorrhoea; and

Blood PRL levels were at least 50μg/L.
Treatment procedure –
crossover design
Subjects randomly received
additional treatment with PGD (45
g/d) followed by bromocriptine
(BMT, 5 mg/d).
 or BMT followed by PGD at the same
dose for 4 weeks each, with an
interval of 4-week washout period
between 2 treatment sessions.

Comparison of serum PRL level
between PGD and BMT
150
90
*
*
*
*
*
60
30
20
30
10
0
1.2
0
150
C
1.0
D
120
Testosterone (ng/L)
Progesterone (ng/L)
B
40
Estradiol (ng/L)
PRL (ug/L)
120
50
A
0.8
0.6
0.4
90
60
30
0.2
0
0.0
PGD
BMT
--------------------Session I
PGD
BMT
---------------------Session I
PGD
BMT
----------------------Session II
Fig 2
PGD
BMT
--------------------Session II
Reduced
magnitude: 24%
of PGD vs. 2128% of BMT
Improvement on hyperPRLrelated adverse events
PGD
(n = 18)
BMT
(n= 18)
p value a
Any improvement
10 (55.6)
3 (16.7)
0.037
Menstrual resumption from
amenorrhoea or oligomenorrhoea
6 (33.3) b
3 (16.7) b
0.441
Alleviation of menstrual pain
2 (11.1) c
0
Recovery from galactorrhea
3 (16.7)
0
n.t. d
n.t. d
Disappearance of facial acne
1 (5.6)
0
n.t. d
Psychopharmacological effects of
PGD in reducing hyperPRL
PRL secretion (ng/ml)
2.0
0 mg/ml
0.5 mg/ml
1.0 mg/ml
5.0 mg/ml
1.8
A
1.6
**
1.4
**
*
**
1.2
1.0
12
24
36
48
Treatment time (hr)
B
PRL
GAPDH
1.0
PRL expression
0.8
0.6
**
0.4
**
0.2
**
0.0
0
0.1
0.5
1
2
PGD (mg/ml)
4
6
PGD inhibits
synthesis and
secretion of
PRL from MMQ
cultured cells.
A
PRL secretion (ng/ml)
1.5
**
++
1.2
##
0.9
0.6
0.3
B
0.0
Control
HAL
HAL + PGD
PGD
2.0
B
PRL expression
1.6
**
++
1.2
##
0.8
0.4
0.0
Control
HAL
HAL + PGD
PGD
Haloperidol, a
D2 antagonist,
abolished the
effects of PGD
in inhibiting
PRL synthesis
and secretion in
MMQ.
A
2.4
PRL secretion (ng/ml)
2.0
1.6
1.2
0.8
0.4
0.0
B
PRL expression
0.16
0.12
0.08
0.04
0.00
0
2
4
PGD (mg/ml)
6
PGD had no
effects on PRL
secretion and
expression in
GH3 that lack
the expression
of D2 receptors
A
D2
GAPDH
D2 receptor expression
0.15
**
*
0.12
0.09
0.06
0.03
0.00
0
0.5
1
PGD (mg/ml)
2
4
B
DAT
GAPDH
0.35
DAT expression
0.30
*
*
2
PGD (mg/ml)
4
0.25
0.20
0.15
0.10
0.05
0.00
0
0.2
6
PGD enhances
the expression
of D2 receptors
and DAT in PC12
cells.
A
Serum PRL level (ng/ml)
30
##
25
20
15
**
**
**
10
5
0
CTRL
0.6
_____
2.5
5
10
___________________
BMT (mg/kg)
PGD (g/kg)
__________________________________
Serum progesterone (ng/ml)
MCP (150 mg/kg)
B
*
40
30
*
20
#
#
*
10
0
CTRL
0.6
_____
2.5
5
10
___________________
BMT (mg/kg)
PGD (g/kg)
__________________________________
MCP (150 mg/kg)
Serum estradiol (E2, pg/ml)
50
C
40
30
#
20
*
#
10
0
CTRL
0.6
_____
2.5
5
10
___________________
BMT (mg/kg)
PGD (g/kg)
__________________________________
MCP (150 mg/kg)
PGD suppressed
hyperPRL in rats
induced by
metoclopramide (MCP,
150 mg/kg daily), a
dopamine inhibitor for
10 days. PGD also
protects against the
decrease of
progesterone, but BMT
did not.
Similar results
were reproduced
in in another
experiment.
The effects of PGD on dopamine
mediators in the pituitary of rats
The effects of PGD on the rat
hypothalamic dopamine system
Immunoreactive
effects of PGD in
the hypothalamus
Herb-drug interactions
6000
Serum CLZ (nM)
A
CLZ alone (n = 4)
PGD + CLZ (n = 5)
5000
4000
3000
2000
1000
0
5000
Serum norCLZ (nM)
B
4000
3000
2000
1000
0
Serum CLZ-N-oxide (nM)
3000
C
2500
2000
1500
1000
500
0
0
3
6
9
12
Time (h)
15
18
21
24
PGD had no
interaction
effects with
clozapine in
in vivo.
PGD and individual herbs inhibit
CYP450s in human liver microsomes
norCLZ
25
norCLZ
8
10
50
15
100
10
10
norCLZ
norCLZ
PGD inhibits
specific CYP450
enzymes
25
25
50
50
CLZ-N-oxide
10
Km (µM)
Ki (mg/ml)
1A2 (norCLZ)
Vmax
(pmol/min/pmol)
28.5  4.7
50.8  0.5
0.9  0.1
Enzyme-reaction
model
Noncompetitive
2C19 (norCLZ)
23.9  1.3
30.9  1.4
0.3  0.0
Noncompetitive
2D6 (norCLZ)
53.1  4.3
12.0  4.0
2.4  0.5
Mix
3A4 (norCLZ)
15.2  0.2
40.2  10.5
0.6  0.1
Mix
3A4 (CLZ-N-oxide)
27.7  3.8
16.1  2.9
0.5  0.1
Mix
CYPs
25
50
Major pharmacologically active
components of PGD
LQ, GA and PF suppress PRL secretion
and synthesis in MMQ cells
Paeoniflorin has
neuroprotective effects
Paeoniflorin has
neuroprotective effects
Glycyrrhetinic acid inhibits
pituitary adenoma
18beta-Glycyrrhetinic acid inhibits
pituitary adenoma
Liquiritigenin also inhibits
pituitary adenoma
Anti-tumor effects of liquiritigenin
on pituitary adenoma
Re-visit clinical trial
PGD as additional therapy to treat
antipsychotic-induced hyperPRL
in women with schizophrenia:
a double-blind, randomized
controlled study
Inclusion criteria






Female aged 18 to 45 years;
had a ICD-10 primary diagnosis of
schizophrenia or schizoaffective disorder;
had been under antipsychotic medications for
at least three months;
Current conditions were stable (PANSS < 60);
had developed at least one overt hyperPRLsymptom: oligomenorrhoea, amenorrhoea,
galactorrhea, and/or decreased sex drive;
serum PRL levels are >24 ng/ml
Treatment procedure

While continuing the current
antipsychotic regimens.

Patients randomly received
additional treatment with PGD
(50 g/d) or placebo for 16
weeks.
HPLC profile of PGD preparation
used in the present study
E
B
A
C
D
F
A: albiflorin
B: paeoniflorin
C: liquiritin
D: liquiritigenin
E: glycyrrhizic acid
F: Glycyrrhetinic acid
Assessment



HyperPRL: Prolactin Related Adverse
Event Questionnaire (PRAEQ).
Psychosis: PANSS.
Extrapyramidal symptoms:
 Abnormal Involuntary Movement
Scale (AIMS)
 Extrapyramidal Symptom Rating
Scale (ESRS).
Hormone Assays






PRL
Estradiol
Progesterone
Testosterone
FSH
LH
Screened (n = 152)
Excluded in pre-randomization (n = 53):
 Prolactin <24 ng/ml (40)
 Non-schizophrenic (5)
 PANSS score >70 (4)
 Did not meet other entry criteria (4)
Randomized (n = 99)
Placebo (n = 50)
Discontinuation at week 8 (n = 16):
 Severe adverse events (3)
 Loss of contact (10)
 Withdrawal (3)
Completed at week 8
(n = 34, 68.0%)
Accumulated discontinuation at
week 16 (n = 24):
 Severe adverse events (3)
 Loss of contact (20)
 Withdrawal (3)
Completed at week 16
(n = 26, 52.0%)
PGD (n = 49)
Discontinuation at week 8 (n = 10):
 Severe adverse events (0)
 Loss of contact (5)
 Withdrawal (5)
Completed at week 8
(n = 39, 79.6%)
Accumulated discontinuation at
week 16 (n = 21):
 Severe adverse events (1)
 Loss of contact (15)
 Withdrawal (5)
Completed at week 16
(n = 28, 57.1%)
Flowchart
of the trial
Table 1. Baseline characteristics of schizophrenic women with symptomatic hyperPRL a
Age (y)
Placebo
(n = 50)
30.2 ± 7.4
PGD
(n = 49)
29.4 ± 7.1
All
(n = 99)
29.8 ± 7.2
Total duration of the illness (m)
45.8 ± 45.8
47.8 ± 49.5
46.8 ± 47.3
Duration of current episode (m)
7.5 ± 7.2
8.5 ± 9.3
8.0 ± 8.3
# of psychotic relapses
1.8 ± 1.8
2.0 ± 2.1
1.9 ± 2.0
# of hospital admissions
1.2 ± 1.1
1.1 ± 0.9
1.1 ± 1.0
Subtypes of diagnosis, n (%)
Paranoid
36 (72.0)
35 (71.4)
71 (71.7)
Residual
9 (18.0)
7 (14.3)
16 (16.2)
Undifferentiated
4 (8.0)
7 (14.3)
11 (11.1)
Catatonic
1 (2.0)
0
1 (1.0)
8 (16.0)
5 (10.2)
13 (13.1)
Amenorrhea
24 (48.0)
18 (36.7)
42 (42.4)
Abnormal menstruation
24 (48.0)
29 (59.2)
53 (53.5)
Galactorrhea
6 (12.0)
7 (14.3)
13 (13.1)
Facial acne and hirsutism
0
2 (4.1)
2 (2.0)
Reduced libido
1 (2.0)
0
1 (1.0)
Breast tenderness
0
1 (2.0)
1 (1.0)
PANSS c
42.0 ± 9.7
42.7 ± 9.3
42.4 ± 9.4
Prolactin (ng/ml)
112.2 ± 45.8
109.9 ± 53.9
111.0 ± 50.1
# of family members having severe
mental diseases, n (%)
HyperPRL-related symptoms, n (%)
b
Table 2. Antipsychotic regimens used at entry in schizophrenic
women with symptomatic hyperPRL
Monotherapy
Placebo
(n = 50)
28 (56.0)
PGD
(n = 49)
26 (53.1)
P value
Combination therapy
22 (44.0)
23 (46.9)
Risperidone
24 (48.0)
28 (57.1)
0.478
Paliperidone
13 (26.0)
11 (22.4)
0.859
Sulpride/amisulpride
10 (20.0)
6 (12.2)
0.438
Olanzapine
5 (10.0)
7 (14.3)
0.730
Ziprasidone
4 (8.0)
3 (6.1)
0.978
Quetiapine
4 (8.0)
2 (4.1)
0.692
Perphenazine
2 (4.0)
1 (2.0)
0.986
Clozapine
0
3 (6.1)
0.234
Chlorpromazine
1 (2.0)
0
0.992
0.927
Table 3. Treatment outcomes of schizophrenic patients with
symptomatic hyperPRL a
Placebo
PGD
t value
P value
PRAEQ b
Baseline
25.6 ± 8.7 (50)
26.2 ± 10.6 (49)
0.303
0.762
Week 8
15.7 ± 8.9 (34)
16.6 ± 9.9 (39)
0.415
0.679
Week 16
15.1 ± 8.5 (26)
10.9 ± 4.6 (28)
2.273
0.027
Baseline
42.0 ± 9.7 (50)
42.7 ± 9.3 (49)
0.329
0.743
Week 8
40.0 ± 8.8 (34)
40.8 ± 7.9 (39)
0.397
0.693
Week 16
38.4 ± 7.5 (26)
39.7 ± 7.8 (28)
0.608
0.546
Baseline
0.9 ± 3.9 (50)
0.7 ± 1.7 (49)
0.305
0.760
Week 8
0.8 ± 4.3 (34)
0.6 ± 1.5 (39)
0.226
0.822
Week 16
2.3 ± 6.5 (26)
0.6 ± 1.6 (28)
1.297
0.201
Baseline
2.2 ± 3.8 (50)
1.4 ± 3.0 (49)
1.161
0.249
Week 8
1.3 ± 2.8 (34)
0.7 ± 1.5 (39)
1.075
0.286
Week 16
0.9 ± 2.2 (26)
1.2 ± 2.3 (26)
0.488
0.628
PANSS b
AIMS b
ESRS b
Table 4. Changes in the proportion of schizophrenic patients having
different treatment outcomes on PRAEQ-measured hyperPRL
Placebo
(n = 50)
PGD
(n = 49)
2 value
P value
Improvement
12 (24.0)
24 (49.0)
8.395
0.039
Unchanging
20 (40.0)
16 (32.6)
Worsening
2 (4.0)
0
Discontinuation
16 (32.0)
9 (18.4)
Improvement
14 (28.0)
19 (38.8)
2.201
0.532
Unchanging
12 (24.0)
9 (18.4)
Worsening
3 (6.0)
1 (2.0)
Discontinuation
21 (42.0)
20 (40.8)
At week 8
At week 16
Changes in the proportion of
patients achieving different
treatment outcomes
Table 5. Changes in serum levels of prolactin and sex hormones in schizophrenic patients with
symptomatic hyperPRL
Variables
Prolactin
(ng/mL)
Estradiol
(pg/mL)
Testosterone
(ng/dL)
Progesterone
(ng/mL)
FSH (IU/L)
LH (IU/L)
Baseline_______________
Placebo
PGD
(n = 50)
(n = 49)
112.2±45.8 109.9 ± 53.9
Week 8________________
Placebo
PGD
a
(n = 30-32)
(n = 37-39) a
101.3 ± 48.4 96.4 ± 69.7
Week 16_______________
Placebo
PGD
(n = 26)
(n = 24) a
92.3 ± 55.1
104.0 ± 68.0
47.9 ± 42.3
36.1 ± 26.3
55.1 ± 62.6
52.9 ± 64.0
67.6 ± 67.2
42.0 ± 25.8
38.2 ± 17.3
35.4 ± 21.0
44.8 ± 22.8
32.3 ± 15.6*
42.5 ± 24.7
30.4 ± 14.4*
1.3 ± 2.5
1.3 ± 3.2
1.0 ± 1.9
0.8 ± 1.1
2.3 ± 3.8
1.4 ± 3.2
5.7 ± 2.5
6.6 ± 3.2
5.6 ± 2.0
8.4 ± 7.7*
5.0 ± 2.6
6.3 ± 1.6*
6.9 ± 5.0
8.1 ± 6.0
9.3 ± 9.6
8.3 ± 4.9
6.9 ± 8.7
7.4 ± 4.7
Conclusions
 PGD is indeed a safe and effective
therapy for antipsychotic-related
hyperPRL, without exacerbating
psychosis and abnormal involuntary
movements.
 Its effect may be associated with the
normalization of related sex hormone
dysfunction, rather than the direct
suppression of elevated PRL.
“B2B” translational research


Bench to Bedside:
modern pharmaceutical
Bedside to Bench: TCM
Bidirectional research
Acknowledgements
 Supported by HMRF, GRF and
HKU intramural funds.
 HK: Marksman and Wang Di
 Beijing: Wang Chuan-Yue, Li
Shengbin
 Xi’an: Tan Qingrong, Wang
Huaihai.
Thank you!
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