Traditional Medicine-2015 Birmingham, UK August 03 – 05, 2015

1. Traditional Medicine-2015Birmingham, UKAugust 03 – 05, 2015 Zhang-Jin Zhang Traditional Medicine 2015

2. 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

3. Peony-Glycyrrhiza decoction, an herbal preparation against antipsychotic-induced hyperprolactinemia: from bedside to bench (“B2B”) Zhang-Jin Zhang, Professor The University of Hong Kong Traditional Medicine 2015, Birmingham

4. 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.

5. 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.

6. HPLC profile of PGD Wang et al., 2012.

7. A pilot trial of PGD to treat HyperPRL (2008)

8. 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.

9. 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.

10. Comparison of serum PRL level between PGD and BMT Reduced magnitude: 24% of PGD vs. 21-28% of BMT

11. Improvement on hyperPRL-related adverse events

12. Psychopharmacological effects of PGD in reducing hyperPRL

13. PGD inhibits synthesis and secretion of PRL from MMQ cultured cells.

14. Haloperidol, a D2 antagonist, abolished the effects of PGD in inhibiting PRL synthesis and secretion in MMQ.

15. PGD had no effects on PRL secretion and expression in GH3 that lack the expression of D2 receptors

16. PGD enhances the expression of D2 receptors and DAT in PC12 cells.

17. 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.

18. Similar results were reproduced in in another experiment.

19. The effects of PGD on dopamine mediators in the pituitary of rats

20. The effects of PGD on the rat hypothalamic dopamine system

21. Immunoreactive effects of PGD in the hypothalamus

22. Herb-drug interactions

23. PGD had no interaction effects with clozapine in in vivo.

24. PGD and individual herbs inhibit CYP450s in human liver microsomes

25. PGD inhibits specific CYP450 enzymes

26. Major pharmacologically active components of PGD

27. LQ, GA and PF suppress PRL secretion and synthesis in MMQ cells

28. Paeoniflorin has neuroprotective effects

29. Paeoniflorin has neuroprotective effects

30. Glycyrrhetinic acid inhibits pituitary adenoma

31. 18beta-Glycyrrhetinic acid inhibits pituitary adenoma

32. Liquiritigenin also inhibits pituitary adenoma

33. Anti-tumor effects of liquiritigenin on pituitary adenoma

34. Re-visit clinical trial PGD as additional therapy to treat antipsychotic-induced hyperPRL in women with schizophrenia: a double-blind, randomized controlled study

35. 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 hyperPRL-symptom: oligomenorrhoea, amenorrhoea, galactorrhea, and/or decreased sex drive; • serum PRL levels are >24 ng/ml

36. Treatment procedure • While continuing the current antipsychotic regimens. • Patients randomly received additional treatment with PGD (50 g/d) or placebo for 16 weeks.

37. HPLC profile of PGD preparation used in the present study A: albiflorin B: paeoniflorin C: liquiritin D: liquiritigenin E: glycyrrhizic acid F: Glycyrrhetinic acid

38. Assessment • HyperPRL: Prolactin Related Adverse Event Questionnaire (PRAEQ). • Psychosis: PANSS. • Extrapyramidal symptoms: • Abnormal Involuntary Movement Scale (AIMS) • Extrapyramidal Symptom Rating Scale (ESRS).

39. Hormone Assays • PRL • Estradiol • Progesterone • Testosterone • FSH • LH

40. Flowchart of the trial

45. Changes in the proportion of patients achieving different treatment outcomes

47. 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.

48. “B2B” translational research • Bench to Bedside: modern pharmaceutical • Bedside to Bench: TCM Bidirectional research

49. 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.

50. Thank you!