Conference on Healthy Gujarat- “Agenda for Actions”December 3rd , 2013

Dept of Health and FW – Govt of GujaratGandhinagar

“ Recent Advances in Experimental Medicine”( Focus on areas for possible convergence )

Dr.B.RavishankarSDM Centre for Research in Ayurveda and

Allied SciencesUdupi

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Why convergence or integration is requited ?

None of the existing systems can meet all the requirements of health care- existence of ‘

therapeutic gap’

Different systems work on different Scientific paradigms-

Example – unitary or reductionists approach of conventional medicine

Holistic approaches of ISM like Ayurveda – combining the approaches may be beneficial

Unique mechanisms of action - possible benefits - through synergestic therapy

Patients acceptability and preference high for integrated approach

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Potential areas of convergence :

Prophylaxis

Diagnosis

Drug therapy

Combination of non-drug therapies and drugs

Requirement : Data generation as Evidence base through experimental studies- both basic and clinical

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Prophylaxis- Concepts of proper daily, seasonal routines advocated in Ayurveda can be integrated

Constitution types – similar to genomic studies – ex- 1

Functional Foods-

Prophylactic measures in ISM

Avoidance of incompatibilities – adoption of the concept of incompatibilities

Drug research- the fundamental concept for drug selection and incorporation to therapeutics is known as

Rasapanchaka . < Rasa < Guna < Veerya < Vipaka and Prabhava are the five attributes considered in candidate plant or formulations .

Interesting recent developments – related to rasapanchaka

Drug related incompatibilities:

Incompatibility of climate, season and soil- (desa- and kala viruddha) –

Incompatibility of drug preparation-(Samskara- viruddha)

Arrangement of order of drug administration - (krama)

Drug preparation method (Paka)

Physical and chemical factors (Samyoga)

Quantitative (mana-virodha)- ghee and honey taken in equal quantity

Qualitative- (karma virodha)- dhataki and danti Gandhinagar Dept of HFW- Dec 3rd 2013 5

B kalpana- the science of formulation in ayurveda is highly sophisticated and formulation factors have tremendous influence over the expression of the biological activity. > 22 types of formulation forms are in vogue

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Combined drug therapy

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Drug action through bio-enhancement (Trikatu): The mechanism of drug bioavailability enhancing effect of Piperine:

a-increased blood supply to the gastrointestinal tract,  b- increased enzymatic activities like gamma-glutamyl transpeptidase which participates in active transport of nutrients across the intestinal cells   c- non-specific mechanisms inhibiting enzymes involving in biotransformation of drugs, preventing their inactivation and elimination (Goldstein, 1984; Esposito, 1984)

d- by increasing the membrane fluidity -   Piperine, or mixtures containing piperine, has been shown to increase the bioavailability, blood levels and efficacy of a number of drugs including ingredients of vasaka leaves, vasicine, sparteine, sulfadiazine, rifampicin, phenytoin and propranolol

Cyclo –Immunosuppression- Table-A and Fig-A

Cyclo-myelosuppression- Table-B

Groups Anti body titre Log2value

Control 6.01 0.23

Cycl control 4.46 0.37*

Cycl + VDAV 5.78 0.29*a

Cycl + ADJ 5.68 0.67

* P< 0.05 Vs- control *a P <0.05 Vs Cyclo

Table- A – Effect of VDAV and ADJ on Cyclophosphamide induced suprression of anti-SRBC antibody in rats/

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AS adjuvant

Disease control

Lipoic acid

Jasad bhasmaJasad

+Betle

Normal control

50

100

150

200

250

300

Basal 1 2 3 4 5 6

Month of Treatment

Blo

od g

luco

se (m

g%)

Normal Control Disease Control Jasad Bhasma

Jasad + Betle Lipoic acid

Effect on fasting blood sugarEffect on fasting blood sugar

Courtesy Dr. Supriya Bhale RaoGandhinagar Dept of HFW- Dec 3rd 2013 9

Normal control

Jasad bhasma

Disease control

Lipoic acidJasad + Betle

25

35

45

55

Basal 1 2 3 4 5 6

Month of Treatment

Ner

ve

con

du

ctio

n v

elo

city

(m

/s)

Normal Control Disease Control Jasad Bhasma

Jasad + Betle Lipoic acid

Effect on nerve conduction velocityEffect on nerve conduction velocity

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Bacopa and Centella extracts increase neuronal branching -Paper 1

Net work and System pharmacology conceptsExample-1

Result a new discipline Quantitative and Systemic Pharmacology- An NIH White Paper by the QSP Workshop Group – October, 2011

Examples of unique mechanisms of action of Ayu drugs

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Modulation of nuclear receptors :Guggulsterone- antagonizes the farnesoid X receptor (FXR), which regulates cholesterol metabolism in the liver

Guggulsterones also modulate the activity of multiple nuclear receptors- involved in steroid hormone regulation- glucocorticoid, progesterone , mineralocorticoid,

androgen and estrogen receptors

Guggulsterone up-regulates the bile salt export pump (BSEP- favours metabolism of cholesterol

to bile acids

The cembranoids (from guggul) lowered the cholate (1)- activated rate of human pancreatic-IB phospholipase A2 (hPLA2), which controls gastrointestinal absorption of fat and

cholesterol

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Multimodal mechanism of action-

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FIG 1. Targets of curcumin. Abbreviations: MEKK, MAPK/ERK kinase kinase; IKK, IB kinase; IB, inhibitory kappa B; CBP, CREB-binding protein; HDAC, histone deacetylase; P, phosphorylation; U, ubiquitination; MAPK, mitogen activated protein kinase; MEK, MAPK/ERK kinase; MKK, MEK kinase; ERK, extracellular signal regulated kinase; JNK, cJun N-terminal kinase; TAK/ASK, transforming growth factor--activated /apoptosis signal-regulated kinase; PI3K, phosphatidylinositol-3-kinase; ISRE, IFN-stimulated responsive element; GAS, IFN activation site; mTOR Mammalian target of rapamycin; PKC, protein kinase C; Keap, Kelch-like ECH-associated protein 1. (Color version of figure is available online.)

Multimodal mechanism of action- 3 ( Effect on networks)

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From : Simone Reuter • Subash C. Gupta • Byoungduck Park • Ajay Goel • Bharat B. Aggarwal. Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr (2011) 6:93–108. DOI 10.1007/s12263-011-0222-1

Effect on Epigenetic factors

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Synergistic pharmacology : Synergy research: approaching a new generation of phytopharmaceuticals-H. Wagner G. Ulrich-Merzenich

Two events initiated synergy research in phytomedicine: first, the new methods of analytical chemistry and molecular biology that have become available during the past decade, and second, an unexpected change of paradigm in chemotherapy that appeared without great attention

Multidrug therapy is already being practiced worldwide in the treatment of AIDS and other infectious diseases,

hypertension, numerous types of cancer and rheumatic diseases

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Review on herb drug interactions

Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs

Examples of drug transporter modulators from plants- curcumin, piperine, silymarin, ginsenosides, catechin and flavonoids etc

Can be an important target for drug formulation development

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From the above facts it becomes clear that data generation through experimental (research) studies are the first requisite to

identify the potential areas for convergence of conventional and Traditional medical systems

Thus there is urgent requirement for the establishment of dedicated research and innovation centres in the field of Ayurveda and Integrative Medicine

Establishment of ISM Innovation and Research Universities would be a welcome initiative

Legislation for dual or multiple medical practice licence is also required

Gandhinagar Dept of HFW- Dec 3rd 2013 20Thank you