Dangers in herbs drug interactions understanding mechanisms to inform management
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Dangers in Herbs-Drug Interactions Understanding mechanisms to inform management. Andrew McLachlan. Centre for Education and Research on Ageing Concord RG Hospital Australia. Faculty of Pharmacy University of Sydney Australia. This presentation. Complementary medicines use

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Dangers in herbs drug interactions understanding mechanisms to inform management

Dangers in Herbs-Drug InteractionsUnderstanding mechanisms to inform management

Andrew McLachlan

Centre for Education and Research on Ageing

Concord RG Hospital

Australia

Faculty of Pharmacy

University of Sydney

Australia


This presentation

This presentation

  • Complementary medicines use

  • People most at risk

  • Investigating herb-drug interactions

  • Understanding and applying the findings


Dangers in herbs drug interactions understanding mechanisms to inform management

Complimentary medicines

Complementary medicines


Dangers in herbs drug interactions understanding mechanisms to inform management

Complementary medicine

Complementary medicines


Dangers in herbs drug interactions understanding mechanisms to inform management

Complementary medicines

Alternative medicines


Australian trends in the use of supplements

CAM

1993*

2000*

2004*

Vitamins (but not calcium or iron)

38 %

36 %

39 %

Herbal medicines

10 %

13 %

21 %

Mineral supplements

9 %

11%

14 %

Soy products

-

-

4 %

Chinese medicines

2 %

3 %

2 %

Homeopathic medicines

4 %

4 %

2 %

Total CAM user (at least one product)

49 %

52 %

52 %

Australian trends in the use of supplements

*data shown as percent respondents who have used these medicines within the last 12 months.

MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and

alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.


Us trends in the use of supplements

US trends in the use of supplements

13% used at least 1 herbal supplements in the last 12 months

n=5860

aged above 65 years

Bruno JJ, Ellis JJ. Herbal use among US elderly: 2002 National Health Interview Survey. Ann Pharmacother. 2005


The issue

The issue

  • 50% of people who reported that they used complementary and alternative therapies also used conventional medicines on the same day

  • 57% did not report the use of complementary therapies to their doctor.

MacLennan AH, Myers SP, Taylor AW.The continuing use of complementary and

alternative medicine in South Australia: costs and beliefs in 2004. Med J Aust. 2006;184:27-31.


Dangers in herbs drug interactions understanding mechanisms to inform management

Herb-drug interactions: potentially important but woefully under researchedE. ErnstEur J Clin Pharmacol 2000: 56: 523-524

  • Why have only so few cases of suspected herb-drug interactions been reported in the medical literature?

  • Truly rare events?

  • Significant unreporting?


Dangers in herbs drug interactions understanding mechanisms to inform management

http://www.pharma.unibas.ch/bio/img/Humor_now_and_then/Humor_Herbal_Medicine_2.jpg


Clinical risk management of herb drug interactions

Clinical risk management of herb-drug interactions

  • Risk identification and assessment

  • Development and implementation of risk reduction strategies

  • Evaluation of risk reduction strategies

De Smet, PAGM. Br J Clin Pharmacol 2006


Clinical significance of herb drug interactions

Clinical significance of herb-drug Interactions

  • Patient characteristics

  • Nature of pharmacodynamic response

  • Mechanism of interaction

  • Safety margin of the interacting herb and drug

  • Quality of the product

  • Size of the dose

  • Duration of therapy

  • Time course of drug interaction

  • Order and timing of administration

PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions:

an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25


Dangers in herbs drug interactions understanding mechanisms to inform management

Understanding the mechanism of a herb-drug interaction allows the

  • prediction of other interactions

  • assessment of clinical significance

  • guide risk minimisation strategies


Study designs used to assess herb drug interactions

Study designs used to assess herb-drug interactions

  • Controlled trials in patients

  • Controlled trials in healthy subjects

  • Case reports or series

  • Animal studies

  • In vitro studies

  • Adverse event data

  • Theoretical

PD Coxeter, AJ McLachlan, CC Duke, BD Roufogalis. Herb-drug interactions:

an evidence based approach. Current Medicinal Chemistry 2004;11:1513-25


Investigating drug interactions

Investigating drug interactions

Type of

study

Mechanism

Clinical

Relevance

Ethical

Issues

Cost

Enzyme, Cells

or microsomes

Animals

Healthy

subjects

Patients


The need to establish quality consort guidelines for reporting

The need to establish qualityCONSORT guidelines for reporting

Gagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions:

An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.


The need to establish quality of herbal medicine product

Herbal medicine product name

Characteristics of herbal product (including part of plant used)

Dose and qualitative description

Quantitative analysis of HMP (including procedures and standardisation)

The need to establish quality of herbal medicine product

Gagnier JJ et al, Reporting Randomized, Controlled Trials of Herbal Interventions:

An Elaborated CONSORT Statement. Ann Intern Med. 2006;144:364-367.


Dangers in herbs drug interactions understanding mechanisms to inform management

Herb-drug interactions with warfarin

  • To investigate the potential herbal-drug interactions with warfarin

  • To examine the effect of herbal medicines on clotting status

  • Commonly used herbal medicines

    • St Johns wort, Asian ginseng

    • ginkgo biloba, ginger

    • cranberry juice, garlic

Jiang et al, Brit J Clin Pharmacol 2004, 2005,


Dangers in herbs drug interactions understanding mechanisms to inform management

Herb-drug interactions with warfarin

  • To investigate the potential herbal-drug interactions with warfarin

  • To examine the effect of herbal medicines on clotting status

  • Commonly used herbal medicines

    • St Johns wort

    • cranberry juice

I will focus on these

herbal medicines

Jiang et al, Brit J Clin Pharmacol 2004, 2005,


St john s wort

St John’s Wort

  • In vitro study: inhibit human CYP2D6, CYP3A4 and CYP2C9 Budzinski et al, Phytomedicine 2000

  • In vivo study in healthy subjects: induce human CYP3A4, CYP2E1, CYP1A2 and P-glycoprotein

  • Case reports: reduce the efficacy of warfarin

    Fugh-Berman & Ernst, Br J Clin Pharmacol 2001


Comparison of german st john s wort products according to hyperforin and total hypericin content

Comparison of German St John’s Wort Products according to hyperforin and total hypericin content

Wurglics et al, J Am Pharm Assoc 2001


St john s wort dose and preparation on herb drug interaction with digoxin

St John’s wort dose and preparation on herb-drug interaction with digoxin

Mueller et al, Clin Pharmacol Ther 2004


Tlc of proprietary st john s wort products

TLC of Proprietary St John’s Wort Products

A: Hypericin;

B: Pseudohypercin;

C: Hyperoside;

D: Rutin;

No. 5: Use in the trial

-A

-B

-C

-D

TLC of different commercial St John’s wort

1 2 3 4 5 6

(British Pharmacopoeia 2001)


Study design

Study Design

  • randomised, open label, three-treatment, three-sequence, crossover design

  • 14-day washout period

  • single 25 mg dose of warfarin

  • with or without treatment with herbal medicines

  • Blood samples collectedat-48, -24, 0 and up to 168 h


Mechanisms of drug interactions

Mechanisms of drug interactions

PHARMACOKINETIC

PHARMACEUTICAL

PHARMACODYNAMIC


Dangers in herbs drug interactions understanding mechanisms to inform management

S-warfarin S-7-hydroxywarfarin

CYP2C9

Park et al, 1998


Effect of st john s wort and asian ginseng on the pharmacodynamics of warfarin

Effect of St John’s wort and Asian ginseng on the Pharmacodynamics of Warfarin

*

*P<0.05

Jiang et al, Brit J Clin Pharmacol 2004


Dangers in herbs drug interactions understanding mechanisms to inform management

S-warfarin PK data shown

Jiang et al, Br J Clin Pharmacol 2004


Dangers in herbs drug interactions understanding mechanisms to inform management

S-warfarin PK data shown

Jiang et al, Br J Clin Pharmacol 2004


Mortality and inr

Mortality and INR

Oden and Fahlen, BMJ 2002


St john s wort can reduce the effectiveness of many medicines

Pretreatment with SJW significantly

St John’s wort can reduce the effectiveness of many medicines

Mills E et al. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ. 2004;329:27-30.


St john s wort can reduce the effectiveness of many medicines1

Pretreatment with SJW significantly

St John’s wort can reduce the effectiveness of many medicines

Jiang X et al. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2004

Mills E et al. Interaction of St John's wort with conventional drugs: systematic review of clinical trials. BMJ. 2004;329:27-30.


Dangers in herbs drug interactions understanding mechanisms to inform management

Rindone and Murphy, Warfarin-Cranberry Juice Interaction Resulting in Profound

Hypoprothrombinemia and Bleeding. Am J Ther 13, 283–284 (2005)


Dangers in herbs drug interactions understanding mechanisms to inform management

*

33% increase in INR response

* p =0.017

Randomsied cross-over clinical trial

12 healthy male subjects

25 mg warfarin dose +/- 2 weeks treatment with cranberry juice extract

MI Mohammed Abdul et al, 2006


Dangers in herbs drug interactions understanding mechanisms to inform management

MI Mohammed Abdul et al, 2006


Dangers in herbs drug interactions understanding mechanisms to inform management

MI Mohammed Abdul et al, 2006


Dangers in herbs drug interactions understanding mechanisms to inform management

Pharmacodynamic Endpoint

Jiang et al, Br J Clin Pharmacol 2004, 2005

MI Mohammed Abdul et al, 2006


Challenges with evidence related to herb drug interactions

Challenges with evidence related to herb-drug interactions

  • Many published studies lack rigorous design

  • May not reflect how complementary medicines are used in practice

  • Not conducted in the patient group of interest

  • Product quality and variability is a key concern

    • Ginkgo biloba (based on EGb 761)

    • St John’s wort (hyperforin content)

  • Lack of surveillance on use (esp in combination)


Avoiding clinical significant herb drug interactions

Avoiding clinical significant herb-drug interactions

  • comprehensive history is essential

  • review and assess evidence

  • appreciate health

  • monitor when herbs or drugs are started and stopped

  • …or doses increased

  • understanding the likely time course of an interaction


In conclusion

In conclusion….

  • Complementary medicine use is increasing

  • Consider the patient perspective

  • Clinical risk management

  • Focus on the people most at risk

  • Investigating herb-drug interactions

    • Understanding mechanisms

    • Evidence of quality

    • Quality of evidence

  • Informed application of the evidence


Acknowledgments

Acknowledgments

St Vincent's Hospital

Sydney

Prof Ric Day

A/Prof Kenneth Williams

Dr Winston Liauw

Clinical trials staff

HMREC

Prof Basil Roufogalis

Peter Coxeter

Dr Xuemin Jiang

Mohammed Abdul Mohi Iqbal

Dr Colin Duke

Dr Alaina Ammit

Dr Gray Peng

Cathy Rich

Claudia Kohlert-Schutt

Vincent Fairfax Family Foundation

The National Health and Medical Research Council (NHMRC)


The university of sydney over 150 years of tradition in education and research

The University of Sydneyover 150 years of tradition in education and research


Dangers in herbs drug interactions understanding mechanisms to inform management

“Show me a drug with no side effects and I’ll show you a drug with no actions”

Sir Derrick Dunlop

Chairman, Committee on Safety of Drugs, UK founder of the Yellow Card System 1964


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