Complementary and Alternative Therapies: Herbal Medicines

Complementary and Alternative Therapies: Herbal Medicines Uncritical enthusiasm Uninformed repulsion Current methodologies not adequate Where is the evidence?

Dr. Ranjit Roy Chaudhury Dr. Urmila Thatte India Challenges in clinical evaluation of alternative medicines

1. Literature search • Paucity of published data • Local Clinical Practice not documented • Good literature search difficult • Journals not indexed, not peer reviewed, poor quality data • Information in local language; needs correct “interpretation”

2. Starting material • Identification and source of herb Bacopa monnieri Centella asciatica Brahmi

2. Starting material • Single herb? Multiple herbs? • Purity: WHO criteria • Continuous Supply, Quality Control and Stability of batches: multi-centric studies • Standardisation of extract: bioassay guided

Chemical markers vs. activity • Estrogenic activity found in a vegetable oil • Plant obtained in July: Active; that obtained in April: Inactive • HPTLC fingerprinting

Chemical markers July: Active vs. April: Inactive Mobile phase - II Mobile phase - I Mobile phase - III

3. Pre-clinical work-up • How much toxicity testing is needed? • Local Regulatory status (India: Categories) • Lack of pre-clinical data: difficulty to extrapolate animal studies

4. Clinical Studies • Which formulation: traditional/new • What dose (crude/extract), regimen, duration: no pre-clinical data, rely on traditional literature

4. Clinical Studies: planning protocol • Sample size • Choosing efficacy and safety variables and end points • Inclusion/Exclusion criteria • Individualisation: constitution

Response to medications depends on prakriti (constitution) Anti-epileptic medication responders Non- responders

4. Clinical Studies: Design • open label • observational • n=1 studies • “Add-on design”: ethics • Blinded studies difficult: Assessor blind possible (ksharasootra)

4. Clinical Studies: use of placebo • Ethics • Difficult to match colour, taste, odour, flavour or formulation of herbal product • Should be truly inert

Ethanol induced gastric mucosal damage in rats : Evans blue leakage in gastric tissue & content (ug/g) IMP011 * NS * placebo *p< 0.05 vs. D/W; NS = not significant vs. IMP-011.

4. Clinical Studies: RCTs • Reduces bias • Difficult to design RCTs for alternative medicines: • Involve complex interventions • Cultural and social influences • Are holistic in nature • Focus on symptoms • Intra & inter variation in responses • Require long duration of therapy

5. Pharmacokinetics • Plasma estimation of “active” molecules difficult • May be more than one “active molecule” • Metabolic changes during absorption possible • “Effect kinetics”: attractive option

6. Ethics • Coinvestigator fromalternative system • Standards of care of control group: HIV research • Informed consent: Meaningful, vernacular, easier? • Attitude towards alternative therapy: safe – patient information sheet may mislead

6. Ethics • Cultural overtones • Translating research findings into components of accessible care • Commercialisation of folklore medicine: rights/share of tribe or community to be given

7. Regulatory Scenario • US FDA & Europe: food supplements; FDA guidelines available • India: • DCGI, State FDAs • Special emphasis on herbal research: Categories

8. Analysis • What degree of improvement to expect? • What should be criteria for defining success? • Comparison with modern potent medicines?

8. Analysis Rate of decrease in wound score ** Student’s unpaired t-test: ** p<0.01vs.GA ** Recurrence of diarrhea in malnourished children *** Chi square test p<0.001 vs. Control

5 rules for Clinical Research in Alternative Medicines • Literature review: look at traditional literature, collate experiential data, proper interpretation • Consult qualified expertise • GMP for investigational products • Plan a good protocol: keep in mind the traditional medicine philosophy • Adhere to ethical and regulatory aspects

Complementary and Alternative Therapies: Herbal Medicines