Tcm model of system biology

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Tcm model of system biology

  1. 1. Master Programme of TCM ICBAS – University of Oporto Heidelberg School of Chinese Medicine Henry Johannes Greten MD, PhD [email_address] TCM as a Model of System Biology New evidence by double blinding?
  2. 2. <ul><li>Functional diagnosis of Chin. Medicine describes biological systems by a mathematical language Heidelberg Model of TCM </li></ul><ul><li>Double-blinded studies in acupuncture are now possible, augmenting the level of evidence </li></ul><ul><li>Acupuncture is more efficient if based on such functional diagnosis </li></ul>Three points, one conclusion system biology of CM is relevant
  3. 3. Present „schematic“ acupuncture – No proof of efficacy <ul><li>Latest meta–analysis of 33 studies on </li></ul><ul><li>acupuncture: „no specific effect“ (Linde 2009) </li></ul><ul><li>No double blinding, no functional diagnosis </li></ul><ul><li>No rational definition of diagnostic criteria </li></ul>
  4. 4. Mathematics in TCM (binary numbering of the I Ging: Leibniz 1643) structural deficiency vs. regulatory deficiency Defining the diagnosis: systemic approach constitution path. factor „ organ pattern“ orbs „ What is the patients „inner nature“ „ What affected the patient?“ „ Which signs and symptoms appear now ?“ 4x2guiding criteria „ snapshot of the actual functional state“ + + + repletio/depletio „ fullness“/„emptiness“ calor/ algor „ heat“/„cold“ extima/intima „ exterior“/„interior“ yin/ yang ? neurovegetative signs humoro-veget. signs neuro-immunolog. stages repletio depletio calor algor repletio depletio calor algor I II III IV V VI F W H M E F W H M E F W H M E F W H M E
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  6. 6.
  7. 7. Binary Numbers formed of Yin and Yang De-mystifying TCM - the Heidelberg model
  8. 8. De-mystifying TCM - the Heidelberg model Summer S Fire Water N Winter W Autumn Spring E Wood Metal
  9. 9.
  10. 10. Summer S Heaven Earth N Winter W Autumn Spring E Hill Lake Thunder Wind Fire Water
  11. 11. Defining the Diagnosis: Periodicity of Regulation 37°C time 38°C 36°C thermostat electric heater water basin 35°C 39°C
  12. 12. yin (depletion) yang (repletion) time WATER METAL FIRE WOOD EARTH1 EARTH 3 EARTH 2
  13. 13. time yin (depletion) yang (repletion) WATER METAL FIRE WOOD EARTH1 EARTH 3 EARTH 2
  14. 14.  Hyper-dynamic sympathetic parasympathetic Cortisol Adrenaline Endorphines enteric NS active Hyper-tone T3, T4 Hypo- tone Hypo-dynamic enteric NS inactive enteric NS inactive 37°C time 38°C 36°C Wood Metal Water Fire
  15. 15. Clinical manifestations of wood high content of energy, upward movement postulated transmitters, hormones/ metabolism: Sympathetic N.S.  , adrenaline  , glycogenolysis  , glucose  , ACTH ira, power of descision, „ the general“ ; stress-, fight-, territorial-, hierarchy and conflict-programms (limbic system) sensory organ and body opening: eye ; sympathetic signs (tarsal- orbitalmuscles), tendency to high intra-occular pressure, mydriasis voice character: shouting ; tends to inspiratory posture, tongue and larynx go down and open with inspiration. „support“ „ ascendant yang“ sensation of extended liver splanchnic nerves (sympathetic n.s.) stimulate the liver, contracting livercapsule, rising pressure of the liver veins, leucozytosis, glycogenolysis „ hepatic orb rises upward and outward“; contraction of the physiological extensors, extension of the thorax with an inspiratory tendency fist-clenching ; flexor muscles of the arm are „physiological extensor muscles“ perfection: nervus increased neuromuscular excitability, hypertone patterns of movement „ flos“= blossom: nails ; impaired microcirculation (TCM: a „rough flow“ of qi and xue) leads to dystrophy rising (blood) pressure increasing heart rate swollen chest Copyright Greten 2003 chinese interpretation ; western equivalent
  16. 16. FIRE WOOD repletion YANG YIN   time depletion WATER METAL HEPATIC TENUINTESTINAL (“small intestine”) FELLEAL CARDIAL PERICARDIAL TRI-CALORIAL (triple ”burner”) PULMONARY CRASSINTESTINAL RENAL VESICAL PRINCIPAL PROBLEM OF REGULATION ORB distribution of fluids in back and lower burner re - generation breath, surface, rhythm surface of guts, conduction of nourishment control of “positive drive” shoulder-, ear-ache, “emotional abdomen” distribution of qi/fluids on sides and burners control of excitation and flow, “stress” suppressed impulse, ambivalence control of emotionality and associativity
  17. 17. Earth: the principle of regulation 1) downregulation 2) target value 3) upregulation © Greten 2003 De-mystifying TCM - the Heidelberg model time yin (depletion) yang (repletion) “ STOMACH” “ SPLEEN” 1 2 3
  18. 18. Clinical manifestations of Earth Yin, tends towards depletion intima horreal orb, transforms, brings the „clear“ upwards, disease like „postprandiale syndrome“ clears humor, pituita symbolizes metabolism „ rises“ „ holds“ the flesh De-mystifying TCM - the Heidelberg model time yin (depletion) yang (repletion) “ STOMACH” “ SPLEEN” 1 2 3 Yang, tends towards repletion extima aulic orb stores, transports brings the „turbid“ downwards needs to be moisturized ---- symbolizes digestion „ sedates“ --- © Greten 2003
  19. 19. Non-linear Aspects of Chinese Medicine Mathematics in TCM (binary numbering of the I Ging: Leibniz 1643) constitution path. factor „ organ pattern“ orbs „ What is the patients „inner nature“ „ What affected the patient?“ „ Which signs and symptoms appear now ?“ 4x2guiding criteria „ snapshot of the actual functional state“ + + + neurovegetative signs humoro-veget. signs neuro-immunolog. stages structural deficiency vs. regulatory deficiency repletio depletio calor algor repletio depletio calor algor I II III IV V VI repletio/depletio „ fullness“/„emptiness“ calor/ algor „ heat“/„cold“ extima/intima „ exterior“/„interior“ yin/ yang ? F W H M E F W H M E F W H M E F W H M E
  20. 20. Weak yin – the effect of a decrease of water in the basin Copyright Dr. Johannes Greten 2003 HSCM, *49-6221-374546, fax 302035 thermostat electric heater 37°C time 38°C 36°C water basin 35°C 39°C
  21. 21. Local : worse on pressure Pathophysiology of calor („heat“) Copyright Dr. Johannes Greten 2003 HSCM, *49-6221-374546, fax 302035 MICROCIRCULATION INCREASED Red tongue Warm sensation Pre-inflammatory state Relative lack of fluids in larger vessels Systemic : changing pain-location Heart rate increases Dry mouth, nose and lung Sparse, concentrated urine Water saving Dry, constipated stool
  22. 22. Mathematics in TCM (binary numbering of the I Ging: Leibniz 1643) structural deficiency vs. regulatory deficiency Defining the diagnosis: systemic approach constitution path. factor „ organ pattern“ orbs „ What is the patients „inner nature“ „ What affected the patient?“ „ Which signs and symptoms appear now ?“ 4x2guiding criteria „ snapshot of the actual functional state“ + + + repletio/depletio „ fullness“/„emptiness“ calor/ algor „ heat“/„cold“ extima/intima „ exterior“/„interior“ yin/ yang ? neurovegetative signs humoro-veget. signs neuro-immunolog. stages repletio depletio calor algor repletio depletio calor algor I II III IV V VI F W H M E F W H M E F W H M E F W H M E
  23. 23. Relevance of Classical Diagnosis <ul><li>Is acupuncture more effective using the classical diagnosis ? </li></ul><ul><li>Can we perform double-blinding in acupuncture ? </li></ul>
  24. 24. Step 1 Diagnostic TCM Diagnosis Marking Points A, B, C Step 2 Therapist Usage of points Randomised order, ABC, BAC, CAB Double-Blinding Acupuncture Step 3 examiner blinding of patient blinding of therapist blinding of examiner
  25. 25. Objective Pain Evaluation (Flexion) 110 112 114 116 118 120 122 124 126 128 130 before treatment immediately after treatment 7 - days Classical Ac, HM Schematic Ac Control Ac - Knee flexion , degrees 0
  26. 26. Chin. Medicine-Based Acupuncture Superior to „Schematic“ Acupuncture <ul><li>Gonarthrosis pain + mobility: 2x better, n>100 </li></ul><ul><li>Pain after tonsillectomy: HM beats standard by 3x </li></ul><ul><li>Sertel et al., Archives of Otorhinolaryngology, in 2009 </li></ul><ul><li>Congestion of the nose: classical points beat unsp. points Sertel et al. , American Journal of Rhinology, 2009 </li></ul><ul><li>Gait improvement in the elderly : classical point significantly effective, sham acu no effect </li></ul>
  27. 27. Chin. Medicine-based Acupuncture superior to „schematic“ acupuncture <ul><li>Sternotomy induced pain: 78 % vs. 16,3% pain reduction (p< 0,001 </li></ul><ul><li> lung function (IVC): + 360 ml vs. + 33ml (N=100, p <0,001 ) (Kick A et al. 2006) </li></ul><ul><li>Walking distance in pAOD : 86,5 % vs. 40% (N= 34, p< 0,001) </li></ul><ul><li> (Buhlmann E et al. AMSTCAR, Shanghai 2006) </li></ul><ul><li>Capillary bloodflow (O2) in pAOD : 2-6 fold enhancement , </li></ul><ul><li>Effects reversible by „counter acupuncture“ (Greten J, Krug A, Kick A, Remppis A, Diehm C, in preparation ) </li></ul><ul><li>Polyneuropathy : 76% of the patients show enhanced nerve conductivity </li></ul><ul><li>Schröder S et. al. European Journal of Neurology) </li></ul><ul><li>Congestive Heart failure: HM better than standard points </li></ul><ul><li>Journal of Acupunture and Tuina Sciences, 2008 </li></ul>
  28. 28. <ul><li>Pharmacotherapy: </li></ul><ul><ul><li>Inhibition of macrophages by coptis through NFkB blockade comparable to Western pharmacology </li></ul></ul><ul><ul><li>CaCo (Cancer-of-Colon) cells: inhibition of NFkB by coptis and scrophularia </li></ul></ul><ul><ul><li>Curcumin: apoptotic effect in neuroblastoma cells </li></ul></ul><ul><ul><li>Scrophularia: inhibition of proinflammatory NFkB </li></ul></ul><ul><ul><li>C. elegans model: anti-oxidant effect of Chinese herbs </li></ul></ul><ul><ul><li>Hesperitine („orange juice“): HERG blockade </li></ul></ul><ul><ul><li>EGCG (green tee) electrophysiologically active </li></ul></ul>Application in pharmacology
  29. 29. <ul><li>functional diagnosis of Chin. Medicine describes biological systems by a mathematical language Heidelberg Model of TCM </li></ul><ul><li>Double-blinded studies in acupuncture are now possible, augmenting the level of evidence </li></ul><ul><li>Acupuncture is more efficient if based on such functional diagnosis </li></ul>Three points, one conclusion system biology of CM is relevant
  30. 30. Subjective Pain Evaluation (WOMAC) treatment after treatment 0 8 9 10 11 12 13 14 15 16 17 18 19 before immediately 3 - days 7 - days Classical Ac (HM) Schematic Ac Control Ac - WOMAC pain score
  31. 31. 12 studies showing specific effects <ul><li>Cho ZH , Chung SC , Jones JP , Park JB , Park HJ , Lee HJ , Wong EK , Min BI </li></ul><ul><li>New findings of the correlation between acupoints and corresponding brain cortices using functional MRI Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2670-3. </li></ul><ul><li>Ernst M , Lee MH </li></ul><ul><li>Sympathetic effects of manual and electrical acupuncture of the Tsusanli knee point: comparison with the Hoku hand point sympathetic effects. Exp Neurol. 1986 Oct;94(1):1-10. </li></ul><ul><li>Huang ST , Chen GY , Lo HM , Lin JG , Lee YS , Kuo CD Increase in the vagal modulation by acupuncture at neiguan point in the healthy subjects. Am J Chin Med. 2005;33(1):157-64. </li></ul><ul><li>Kim MR , Kim SJ , Lyu YS , Kim SH , Lee YK , Kim TH , Shim I , Zhao R , Golden GT , Yang CH </li></ul><ul><li>Effect of acupuncture on behavioral hyperactivity and dopamine release in the nucleus accumbens in rats sensitized to morphine. Neurosci Lett. 2005 Oct 14;387(1):17-21. </li></ul><ul><li>Kim YK , Lim HH , Song YK , Lee HH , Lim S , Han SM , Kim CJ </li></ul><ul><li>Effect of acupuncture on 6-hydroxydopamine-induced nigrostratal dopaminergic neuronal cell death in rats. Neurosci Lett. 2005 Aug 12-19;384(1-2):133-8. Lee DC , Lee MO , Clifford DH </li></ul><ul><li>Cardiovascular effects of acupuncture in anesthetized dogs. Am J Chin Med (Gard City N Y). 1974 Jul;2(3):271-82. </li></ul><ul><li>Lee DC , Lee MO , Clifford DH </li></ul><ul><li>Modification of cardiovascular function in dogs by acupuncture: a review. Am J Chin Med (Gard City N Y). 1976 WINTER;4(4):333-46. </li></ul><ul><li>Lee JH , Beitz AJ </li></ul><ul><li>The distribution of brain-stem and spinal cord nuclei associated with different frequencies of electroacupuncture analgesia. Pain. 1993 Jan;52(1):11-28. </li></ul><ul><li>Lee MY , Lee DC , Kim S , Clifford DH </li></ul><ul><li>Cardiovascular effects of acupuncture at Tsu San Li (St-36) in dogs. J Surg Res. 1975 Jan;18(1):51-63 </li></ul><ul><li>Lee SC , Yin SJ , Lee ML , Tsai WJ , Sim CB </li></ul><ul><li>Effects of acupuncture on serum cortisol level and dopamine beta-hydroxylase activity in normal Chinese. Am J Chin Med. 1982;10(1-4):62-9. </li></ul><ul><li>Litscher G Computer-based quantification of traditional chinese-, ear- and Korean handacupuncture: needle-induced changes of regional cerebral blood flow velocity. Neurol Res. 2002 Jun;24(4):377-80. </li></ul><ul><li>Park HJ , Lim S , Lee HS , Lee HJ , Yoo YM , Lee HJ , Kim SA , Yin CS , Seo JC , Chung JH </li></ul><ul><li>Acupuncture enhances cell proliferation in dentate gyrus of maternally-separated rats. Neurosci Lett. 2002 Feb 22;319(3):153-6. </li></ul><ul><li>Park HJ , Chae Y , Jang J , Shim I , Lee H , Lim S </li></ul><ul><li>The effect of acupuncture on anxiety and neuropeptide Y expression in the basolateral amygdala of maternally separated rats. Neurosci Lett. 2005 Apr 4;377(3):179-84. Epub 2005 Jan 6. Toda K, Ichioka, M Electroacupuncture: relations between forelimb afferent impulses and suppression of jaw-opening reflex in the rat. Exp Neurol. 1978 Sep 1;61(2):465-70. Toda K, Ichioka M, Suda H, Iriki A Effects of electroacupuncture on the somatosensory evoked response in rat. Exp Neurol. 1979 Mar;63(3):652-8. Toda K, Ichioka M, Iriki A, Suda H Electroacupuncture effects on the field potentials in the caudal part of the spinal trigeminal nucleus evoked by tooth pulp stimulation in rat. Exp Neurol. 1979 Jun;64(3):704-9. Toda K, Ichioka M Afferent nerve information underlying the effects of electroacupuncture in rat. Exp Neurol. 1979 Aug;65(2):457-61. Toda K, Ichioka M, Iriki A Effective conditions of electroacupuncture stimulation for suppressing toothpulp-evoked jaw-opening reflex in the rat. Bull Tokyo Med Dent Univ. 1980 Jun;27(2):111-9. Toda K, Suda H, Ichioka M, Iriki A Local electrical stimulation: effective needling points for suppressing jaw opening reflex in rat. Pain. 1980 Oct;9(2):199-207. </li></ul>

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