Efficacy and Mechanism of XuanXia on Opiate Addiction

1
Efficacy and Mechanism ofXuanXia on Opiate
Addiction

• National Foundation for New Drug R D, China
• WHO Collaborating Research Center for
  Psychosocial Factors, Drug Abuse and Health,
  China
• Mental Health Institute, Hunan Medical
  University, China
• National Institute on Drug Dependence, China
• Fortune United Enterprises Ltd.
• 1999.4

2
Outline

• Introduction
• TCM theory regarding drug addiction
• Views of Western Medicine regarding drug
  addiction
• Modern TCM theory and mechanisms applied to use
  of XuanXia as a dietary supplement in
  detoxification and rehabilitation treatment of
  drug addiction
• Mechanisms of XuanXia in relieving protracted
  (secondary) withdrawal symptoms and psychological
  craving
• Pharmacological study of XuanXia
• Toxicology of XuanXia
• Clinical studies of XuanXia
• Contents and ingredients of XuanXia safe levels
  of trace heavy metals no addictive substances
• A prescriptive dosage of XuanXia

3
Introduction

• Illicit drug abuse has become a public health
  problem worldwide. Development of an effective
  agent for opiate addiction is a crucial mission
  of pharmacologists. Although many detoxification
  agents have become available, no established
  agent meets the preferred criteria of safety,
  efficacy, and freedom from post-treatment
  substance dependency. Moreover, there is no
  satisfactory agent for relieving and treating the
  protracted (secondary) withdrawal symptoms and
  psychological craving that cause relapse.

4

• Under the guidance of the theory of Traditional
  Chinese Medicine(TCM), and working from Yang
  Jitais (a famous Chinese doctor 200 years ago)
  secret recipe, Chinese researchers have developed
  a pure herbal compound called XuanXia, which
  consists of twenty herbs. XuanXia has no
  narcotics, psychotropic agents, or any herb that
  can produce substance dependency. In comparison
  with established substitution agents, XuanXia is
  very effective as a dietary supplement in
  relieving acute and protracted withdrawal
  symptoms and psychological craving, with few and
  typically mild side effects, and with no
  post-treatment dependency on XuanXia. Moreover,
  there is no rebound after discontinuation of
  XuanXia treatment.

5
TCM Overview of Normal Human Physiology
Qi and Blood Five Zang- organs Six
Fu- organs Meridians
transforms into
The kidney is the origin of the congenital
constitution
Conge- nital Qi
warms
Yin
Yang
promotes
The spleen provides the material basis of
the acquired constitution
nourishes
Balance
6
TCMs Understanding of drug addiction
All channels boiling Qi-Blood quickly
flowing Zang-Fu organs pseudo-vigorous
Impairs spleen and kidney Damages vital essence
and Qi Causes insufficiency of congenital Qi
Deficiency in root and Excess in
superficiality Upward Floating of
Deficiency- Yang
Pungent and perfume Bitter and warm
Narcotic Ingested
Euphoria
Disorder of Qi-Blood Disharmony of
Zang-Fu Imbalance of Yin-Yang
Kidney fails to transform into vital
essence Spleen fails to nourish vital
essence Further damage to vital essence and Qi
Congenital Qi fails to rise
Narcotic Cut off
Withdrawal symptoms
7
Action Position of XuanXia
Deficiency in root and Excess in
superficiality Upward Floating of
Deficiency- Yang
Impairs spleen and kidney Damages vital essence
and Qi Causes insufficiency of congenital Qi
Pungent and perfume Bitter and warm
All channels boiling Qi-Blood quickly
flowing Zang-Fu organs pseudo-vigorous
Narcotic Ingested
Euphoria
XuanXia
Disorder of Qi-Blood Disharmony of
Zang-Fu Imbalance of Yin-Yang
Congenital Qi fails to rise
Kidney fails to transform into vital
essence Spleen fails to nourish vital
essence Further damage to vital essence and Qi
Narcotic Cut off
8
Modern Medicines Understandingof Drug Addiction

• The exact mechanism of addiction is not yet fully
  understood. There are several hypotheses,
  including condition theory, enzyme induction
  hypothesis, receptor hypothesis, nerve and
  transmitter hypothesis, among others. Each
  hypothesis has its own bases, and is supported by
  certain experiments and clinical observations.

9
Physiological Actions ofEndogenous Opioid
Peptides
1. DA system (dopaminergic central nervous
system) 2. NA system (noradrenalin
nor-adrenergic system) 3. 5-HT system (serotonergi
c system heart, brain, bloodvessels, liver) 4.
Ach system (acetyl choline cholinergic
system) 5. GABA system 6. H--Y system 7.
Thyroid system 8. Ca2passage system (blood
vessel caliber heart rate myocardial
compliance) 9. AC-cAMP system (intracellular
messenger) 10.G-protein system
Endogenous opioid peptides
Opiate receptors
Balance
10
1. NA system 2. DA system 3. 5-HT system 4. Ach
system 5. GABA system 6. H--Y system 7.
Thyroid system 8. Ca2passage system 9. AC-cAMP
system 10.G-protein system
Opiate receptors
Endogenous opioid
New Balance
Exogenous opiate

11
1.NA system 2.DA system 3.5-HT system 4.Ach
system 5.GABA system 6.H--Y system
7.Thyroid system 8.Ca2passage system 9.AC-cAMP
system 10.G-protein system
Opiate receptors
Endogenous opioid
Balance
Exogenous opiate
Withdrawalsymptoms
Cut Endogenous opioid off Exogenous
opiate

12
New TCM Hypothesis Regarding XuanXias Action in
Treatment of Opiate Addiction

• The essential actions of Chinese medicine are
  explained as two-way effects and a
  self-adjustment model. Two-way effects means
  most medical herbs contain ingredients with
  two-way remedial effects that are opposite to one
  another. Self-adjustment means the body has
  the functional capability of self-adjusting,
  self-balancing, and self-maintaining. According
  to this model, the effectiveness of a medical
  herb is determined by the condition of the
  treated organism. When the condition of the
  organism is very active, the herbs stimulation
  of the organism is weakened, but the repression
  of the herbs effects is stimulated. Conversely,
  when the condition of the organism is repressed,
  the action of the medical herb is strengthened.
  

13

• Based upon the aforementioned rule, XuanXia
  contains several herbs with two-way effects.
  XuanXia, used as a dietary supplement in
  detoxification and rehabilitation of opiate
  addiction, is very effective in restoring the
  endogenous opioid and monoamine systems directly
  or indirectly to their baseline condition and
  function. In consequence, all systems and
  systemic functions regain a healthy new balance,
  withdrawal symptoms and craving are relieved, and
  body resistance is improved.

14
The Mechanism of XuanXia in Relieving Protracted
Withdrawal Symptoms and Psychological Craving
Persistent Up-Regulation of Opiate and Dopamine
ReceptorsMulti-System Imbalances(Continued
Underlying Dependency Drug-Seeking Behavior
Psychosocial Maladjustment Deficiency of vital
Qi)
After detoxification
Damaged OrganismDeficiency of both Spleen and
Kidney Cardiovascular, Renal, and Immune
Disregularities
AnxietyInsomniaPhysical painIndigestion
Protracted Withdrawal Symptoms
XuanXia
PsychopathiaSocial MaladjustmentAlteration of
ValuesRisk-Taking Behavior
Taking narcoticBrief comfort/relief
Psychological craving
15
Mechanism of XuanXiain Opiate Detoxification
Treatment
XuanXia
1.NA system 2.DA system 3.5-HT system 4.Ach
system 5.GABA system 6.H--Y system
7.Thyroid system 8.Ca2passage system 9.AC-cAMP
system 10.G-protein system

New Health Balance
Opiate Receptors

Endogenous Opioid
Reduced withdrawal symptoms and craving
16
Efficacy of XuanXia in AlleviatingAcute
Withdrawal Symptoms inMorphine-Dependent Rats
17
Mental Health Institute, Beijing Medical
University

• A. Normal control group
• B. Non-treatment group
• C. Clonidine group
• D. High-dosage XuanXia gr.
• E. Medium-dosage XuanXia gr.
• F. Low-dosage XuanXia gr.

18
Naloxone Challenge Test
XuanXia
Naloxone
No withdrawal symptoms were induced
Morphine-dependent Monkey
Challenge Test
19
The Composition of XuanXiaAnd Its Actions

• Composition
• Rhizome Corydalis, Rhizome Corydalis
  Decumbentis, Fructose Vschisandrace, Rhizome
  Gastrodiae, Radis Astragal, Cordyceps, Rhizoma
  Chuanxing, Radis Codonopsis, etc.
• Actions
• Relief of withdrawal symptoms and craving in
  detoxification and rehabilitation from opiate
  addiction
• Strengthening of the bodys resistance

20
Pharmacological Actions of Some of XuanXias
Ingredients

• Actions on the central nervous system
• Actions on the neuroendocrine system
• Actions on the cardiovascular system
• Actions on the digestive system
• Actions on the immune system
• Improvement of the organisms adaptive capability

21
The Actions of XuanXia Within theCentral Nervous
System
Pain relief

Corydalis B
Sedation and sleep induction
XuanXia
Gastrodin


Anticonvulsant
Schisandrin C
Neuroendocrinic regulation

Quinquonoside
22
Corydalis B and Its Molecular Structure (one of
the active ingredients in XuanXia)
Corydalis B
C12H25NO4 335.42
23
Relationship Between the Chemical Structure of
Corydalis B and Its Pharmacological Actions

• Researchers have compared Corydalis Bs five
  types and 38 analogs. The research results
  showed that the integrity of Corydalis Bs
  molecular structure plays an important role in
  its pharmacological actions. The methoxies in 9
  and 10 position have specificity they are
  active radicals. The saturation of the third
  loop is the key to the pharmacological action.
  Based on the connection between different
  chemical structures and their curative effects,
  tetrahydroprotoberberine has been found to have
  tranquilizing effects. This suggests new paths
  for the development of new medicines for mental
  diseases.

24

• The actions of Corydalis B are different
  depending on its different isomers. Levorotation
  has been shown to ease pain and tranquilize.
  High doses can induce tremor in monkeys. Both
  levorotation and dextrorotation can raise the
  seizure threshold to challenge with strychnine
  (strychnine is a known pro-convulsant) --
  reducing the convulsive action of strychnine.

25
Pharmacological Actions of Corydalis B

• Central nervous system actions
• Pain alleviation
• Sedation and sleep induction
• Anti-convulsant action
• Neuro-transmitter regulation in brain
• Neuroendocrine system actions
• Regulation of hypothalamic-pituitary-adrenal
  axis
• Regulation of hypothalamic-pituitary- gonadal
  axis
• Regulation of hypothalamic-pituitary- thyroid
  axis

26
Pharmacological Action of Rhizome Corydalis
Total Alkalid

• Cardiovascular effects
• Dilation of coronary arteries
• Increase in coronary blood flow
• Decrease in blood pressure and peripheral
  vascular resistance
• Anti-arrhythmic effect
• Digestive effects
• Anti-ulcerative effect
• Inhibition of gastric secretion
• Regulation of gastric and intestinal mobility

27
Comparison Between Corydalis Bs Actions and
Morphines Actions On the Central Nervous System
--------------------------------------------------
------------------------------ Corydalis
B Morphine ---------------------------------------
----------------------------------------- Active
Receptor Position extensive
specific Selectivity weak powerful
Analgesic effect weak powerful Sedation
powerful less powerful Duration of
action long short Mechanism blocks
DA morphine - receptor in brain receptors ---
--------------------------------------------------
---------------------------
28
One of the Active Ingredients in
XuanXia, Tetramethylpyrazime and Its Molecular
Structure
29
Pharmacological Actionsof Tetramethylpyrazime

• Actions on the cardiovascular system
• Dilation of coronary arteries
• Increase in coronary blood flow
• Decrease in myocardial oxygen consumption
• Reduction in peripheral vascular resistance
• Actions on the blood/brain barrier (BBB)
• Increase in cerebral blood flow
• Decrease in brain tissue damage

30
Mechanism of Tetramethylpyrazime Acceleration
of Endogenous Opioid Peptide Excretion Enhanced
permeability of BBB versus other alterations in
BBB
Tetramethylpyrazime
Increase in cerebral blood flow Reduction in
brain damage
Blood/Brain Barrier

Improved recovery of brain cell function
? Improved production ofendogenous opioid
peptides?
31
Actions of XuanXia On the Neuroendocrine System
XuanXia



Hypothalamus ? Pituitary ? Gonad
Hypothalamus ? Pituitary ? Adrenal
Hypothalamus ? Pituitary ? Thymus
Radix Morindae Officialis
Zingerone
Lcariin
32
Actions of XuanXia On the Cardiovascular System

• Dilation of coronary arteries
• Increase in myocardial blood flow
• Increase in myocardial contraction
• Decrease in myocardial oxygen (MVO2) consumption
• Anti-arrhythmic effect

Pannaquilon

Angelic acid
XuanXia

• Decrease in peripheral vascular resistance
• Improved microcirculation
• Reduction in blood pressure

Tetramethylpy- razime
33
Actions of XuanXia On the Digestive System
Anti-ulcerative effects

Polysaccharide of Radix Codonopsis glycyrrhizic ac
id, etc.
XuanXia
Inhibition ofgastric secretion


Regulation of gastricand intestinal motility
34
Actions of XuanXia On the Immune System
Weight of immune system organs
Polysaccharide of Herba Epimedii

Polysaccharide of Cordyceps
Humoral immunity

XuanXia
?
Polysacharide of Radix Angelicae Sinensis
Cellular immunity

Polysaccharide of Ganoderma
Mononuclear phagocyte

Natural killer T lymphocytes
Astraglan
35
XuanXias Support of an Organisms Adaptive
Capability
Anti-fatigue

Ginsenosides
Tolerance tooxygen deficit

XuanXia

Polysaccharide of Cordyceps
Tolerance of high or low temperature

Anti-stress
Astraglan

Anti-radiation
36
The Toxicology of XuanXia

• Pharmaceutical Research Institute, Hunan, China

37
Toxicity Tests On XuanXia

• Acute toxicity test
• The highest tolerance dose tested was
  600g/kg/day of XuanXia (equal to 150 times the
  clinical dose for
• XuanXia). The test found no toxicity or
  side effects in the XuanXia test subjects.
• Long-term toxicity test
• XuanXia was infused into rats stomachs at the
  dose of 200g/kg/day (equal to 50 times the
  clinical dose for
• XuanXia), for 30 days. No toxicities or
  side effects were observed in the test-subject
  rats. Routine blood examinations and
  pathological examinations of liver, kidney,
  heart, stomach, spleen, adrenal gland, pancreas,
  ovum, testis, and lung in the test-subject rats
  were normal.

38
Clinical Research

• Mental Health Institute, Hunan Medical University
  
• WHO Collaborating Research Center for
  Psychosocial Factors, Drug Abuse and Health

39
A Comparative Study of the Effect of XuanXia
onWithdrawal Symptoms and Craving for Heroin

• Objectives
• To evaluate XuanXias efficacy as a dietary
  supplement in relieving withdrawal symptoms and
  craving in detoxification and rehabilitation from
  heroin addiction.
• To determine side effects of XuanXia in using it
  as a dietary supplement in detoxification and
  rehabilitation from heroin addiction.
• Method
• Forty-two heroin addicts were randomly assigned
  to two groups for detoxification and
  rehabilitation a XuanXia group (21 cases) and a
  buprenorphine group (21 cases).
• All patients in the two groups received relapse
  prevention counseling in the 2- week inpatient
  phase.

40
Withdrawal Symptoms
41
Psychological Craving
42
Clinical Trial of XuanXia in Heroin
Detoxification Treatment
National Institute on Drug Dependence Beijing
Medical University
43
Required criteria for development of
new TCM for opiate detoxification 1. New TCM
compound must be non-narcotic without any
ingredient with dependence-producing
properties 2. The individual herbs composed in
the compound should accord with TCM
theory 3. It should be effective for
detoxification and without severe adverse
drug reactions 4. Its pharmaceutical quality
should be stable and controllable.
44
Method a multi-center, double blind and double
dummy controlled clinical trial and open trial of
XuanXia Total of 404 cases (male 305, female 99)
of heroin addicts with range of ages 18-48 years
old were included. 201 cases were in controlled
trial group (100 cases with XuanXia, 70 cases
with lofexidine as a positive control and 31
cases with placebo as a negative control), 203
cases were in open trial group with XuanXia.
45
Table1. The effective rates() of
treatment ________________________________________
___________________ Controlled trial
Controlled trial Open trial Day of
Treatment XuanXia Lofexidine
XuanXia Placebo XuanXia
(n69) (n70)
(n31) (n31)
(n203) __________________________________________
___________________________ 3-4
31.88 24.29 25.81
6.45 15.27 5-7
69.57 55.71 58.06
9.68 63.05 8
86.96 91.43
74.19 12.90 78.82
9 97.10 94.29
74.19 12.90 87.19
10 100.00 98.57
83.87 19.35
91.63 ____________________________________________
_________________________ Plt0.05 Plt0.01
Plt0.001
46
Total scores of withdrawal syndromes
before and during treatment.
Day of medication Plt0.01
Plt0.001
47
Total scores of withdrawal syndromes before and
during treatment.
Day of medication
Plt0.05
48
Scores of craving before and during
treatment. Day of
medication
49
Scores of craving before and during
treatment. Day of
medication
50
Scores of anxiety before and during
treatment. Day of Medication
51
Scores of insomnia before and during
Treatment Day of medication
52
Scores of ostealgia and myalgia before and
during treatment Day of medication
53
Scores of lacrimation before and during
treatment. Day of medication
54
Scores of diarrhea and abdominal pain and
diarrhea. Day of
medication Plt0.05
55
Contents of XuanXia Safe Levels of Trace Heavy
Metals No Additive Substances
Beijing Medical University

• Heavy metals
• Traces of thirteen kinds of heavy metals such as
  Hg,Sn,Se,Li, etc. can be detected in XuanXia.
  All levels of the heavy metals in XuanXia meet
  health standards for safe use.
• Addictive substances
• No narcotics or other addictive herbs or other
  substances are present in XuanXia.

56
Future Research Planned on XuanXia

• Exploration of XuanXias biological mechanisms in
  detoxification and rehabilitation treatment of
  opiate addiction
• Identification of the active ingredients in the
  formula of XuanXia and monomers for relieving
  withdrawal symptoms and psychological craving
• Identification of the active ingredients from
  various Chinese medicinal materials development
  of a chemical database related to XuanXia
• Intensification of research and development on
  the applications of fundamental theories of
  modern Chinese herbal medicine to treatment of
  alcohol and drug addiction

57
Comparison Between XuanXia and Traditional
Therapy for Relief from Opiate Addiction
Agent Course
Process
Result XuanXia (pure natural
7-10 days Safe, no pain,
Relief of withdrawal plant without
consciousness symptoms
and any opiate) tolerant
psychological craving

improved physical recovery Substitution
therapy (narcotic 7 days
Safe, no pain, No
relief of psychological substitution drug)
the rate of taking
craving substitute drug-
drug again is higher dependence or
relapse after stopping
treatment Hibernation therapy (sedative-hypnotic
) Additional Dangerous
No relief of withdrawal
post-
symptoms and
hibernation
psychological craving
treatments
frequent relapse
58
Use of XuanXia

• Indication
• Symptoms of withdrawal from opiate
  addiction,e.g. nausea or vomiting, muscle-ache,
  lacrimation or rhinorrhea, pupillary dilation,
  piloerection, sweating, diarrhea, yawning, fever,
  insomnia, etc.
• Psychological craving after quitting use of
  opiate
• Physical weakness associated with drug abuse
• Dosage/use
• The dosage schedule should be determined
  individually and adapted to the patients drug
  use history and treatment responses, and should
  consider the concentration of XuanXia in the
  capsules to be used.
• Day 1 - Day 5 6 pills/6 hours
• Day 6 - Day10 4 pills/8 hours
• Take XuanXia at least 5 hours prior to symptoms
  of withdrawal occur.

59

• Characteristics of XuanXia
• Safe
• Effective
• Results in no substance-dependency
• Convenient Can be administered on an outpatient
  basis
• Precautions
• Use under supervision of physician for pregnant
  women or patients with history of serious heart
  disease or high blood pressure.
• Increase nourishment and avoid raw, cold, or
  acidic food.
• Drink honey-water before taking each dose of
  XuanXia to increase efficacy and reduce
  constipation.
• Insomnia, restlessness, and anxiety may be
  experienced in such cases, mild tranquilizers
  are recommended under supervision of physician.
• For rehabilitation (maintaining abstinence and
  further reducing psychological craving), it is
  recommended that patients should continue to take
  a half-dosage of XuanXia for another 20 days
  following 10-day detoxification treatment.
  Dosage 3 times each day, 3 pills each time,
  depending on individual patients drug use
  history, treatment response, and concentration of
  XuanXia capsules used.